key: cord-0697663-akfrbmdu authors: Xiu, N.; Qian, L.; Sun, R.; Huang, B.; Dong, X.; Xiao, Q.; Zhang, Q.; Lu, T.; Yue, L.; Chen, S.; Li, X.; Sun, Y.; Lu, L.; Xu, L.; Yan, L.; Yang, M.; Xue, Z.; Liang, S.; Ding, X.; Yuan, C.; Peng, L.; Liu, W.; Yi, X.; Lyu, M.; Xiao, G.; Xu, X.; Ge, W.; He, J.; Fan, J.; Wu, J.; Luo, M.; Chang, X.; Pan, H.; Cai, X.; Zhou, J.; Yu, J.; Gao, H.; Xie, M.; Wang, S.; Ruan, G.; Chen, H.; Su, H.; Mei, H.; Luo, D.; Zhao, D.; Xu, F.; Li, Y.; Zhu, Y.; Xia, J.; Hu, Y.; Guo, T. title: Multi-organ Proteomic Landscape of COVID-19 Autopsies date: 2020-08-19 journal: nan DOI: 10.1101/2020.08.16.20176065 sha: 39f3eeef5a0c8dbae029302f92357eece333164b doc_id: 697663 cord_uid: akfrbmdu The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome with SARS-CoV-2 nucleocapsid (N) protein, which could be sequestered by viruses to 275 promote their replication (Gordon et al., 2020) . Mitochondrial proteins known to be 276 targeted by viruses to enhance their replication (Williamson et al., 2012) . The 277 interaction between SARS-CoV-2 Nsp9 and eIF4H may indicate the inhibition of host 278 mRNA expression (Gordon et al., 2020) . The interaction between Nsp9 and MIB1 279 may mediate the delivery of viral DNA through nuclear pore complex (Gordon et al., 280 2020). IL17RA is associated with elevation of collagen and pulmonary fibrosis, and 281 its inhibitor has been reported to reduce fibrosis in SARS infection (Mi et al., 2011) . 282 The interaction between Orf10 and ZYG11B may be hijacked for degradation of virus 283 restriction factors or be blocked to protect itself from degradation (Gordon et al., 284 2020). 285 We found that spleen and lung exhibited similar immune response patterns. T 303 Compared with the other organ types, the number of differentially expressed 304 proteins in testes was negligible. Only ten proteins were downregulated ( Figure 7A ). report (Yang et al., 2020) . We also found five down-regulated proteins related to is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. were examined by at least two senior pathologists independently. A total of 144 386 microscopy-guided dissection samples were analyzed from 73 specimens, including 387 heart (9 specimens), lung (15 specimens), liver (10 specimens), kidney (10 388 specimens), spleen (9 specimens), testis (5 specimens), and thyroid (15 specimens), 389 see Tables S1, S2. We also collected 74 control samples from archived blocks of 56 390 non-COVID-19 patients before December, 2019 (Tables S1, S2). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint peptides from each of the 218 tissue samples, and 37 technical replicates, 34 pooling 404 samples including common pooled samples and tissue specific pooled samples (Table 405 S2) were taken for the following TMTpro 16plex labeling based proteomics analysis. 406 The common pooled samples were prepared by mixing equal amount of peptide from 407 6 different human organs including testis, lung, kidney, spleen, heart and liver. The to 10 ppm, and product ion mass tolerance was set to 0.02 Da. Other parameters in 433 Proteome Discoverer analysis are identical to our previous study (Shen et al., 2020b) . 434 The grouped abundance ratio of 15 tissue samples to the pooled sample in the same 435 batch was selected as the value of proteins in the protein matrix for the statistical 436 analysis. As for the lung, spleen, liver, heart, kidney and testis samples, the pooled 437 sample for ratio calculation was chosen as the common pooled sample in the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint the MS acquisition, we analyzed mouse liver protein digests for MS instrument 448 performance evaluation every two batches, and analyzed MS buffer A (2% 449 ACN/0.1% formic acid) as blanks every six LC-MS/MS injections; iii) We random 450 distributed the peptide samples from every organ of COVID-19 patients and non-451 COVID-19 patients into each batch; iv) For data analysis, we calculated the median 452 coefficient of variation (CV) of the proteomics data for reproducibility. As for the 453 pooled controls, we calculated the CV by the log2(abundance) of quantified proteins 454 in the pooled controls of each organ ( Figure S3B ). The pooled samples for CV 455 calculation was the same as the ones for grouped ratio calculation. As for the technical 456 replicates, we calculated the CV by expression ratio of quantified proteins in the 457 technical replicates of each sample ( Figure S3C ). Besides, unsupervised clustering for 458 the proteomics data were performed, including heatmapand tSNE ( Figures S3D, E) . selection was that the adjusted p value should be less than 0.05 and |log2FC| should be 471 larger than log2(1.2). Statistical analysis was performed using R (version 3.6.3). Pathway/network analysis 474 The pathway enrichment was analyzed by either ingenuine pathway analysis is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Lin, H., and Cao, X. (2020). Nuclear innate sensors for nucleic acids in immunity and inflammation. 549 Immunol Rev. Morohoshi, A., Miyata, H., Shimada, K., Nozawa, K., Matsumura, T., Yanase, R., Shiba, K., Inaba, K., is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Shao, W., Guo, T., Toussaint, N.C., Xue, P., Wagner, U., Li, L., Charmpi, K., Zhu, Y., Wu, J., Buljan, M., is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Figure S4 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Multi-organs proteomic changes (supple for Figures 6 and 7 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. To investigate the virus induced pathologic features at the protein level, we first focused on 70 the lung proteome. As the entry of the virus, the known ACE2 receptor and cathepsin L1 (CTSL) 71 for SARS-CoV-2 1 , known C-type lectin domain family 4 member L(CD209) and member M 72 (CLEC4M) receptors for SARS 2,3 were identified in the lung proteome in this study. Interestingly, 73 ACE2, CD209 and CLEC4M were not significantly dysregulated in the lung compared with other 74 organs ( Figure 2C ). This might be associated with the multiple functions of these receptors. ACE2 75 is not only the receptor for SARS-CoV-2, but also regulate the inflammation response. It could 76 directly mediate the macrophage inflammatory function and its angiotensin converting activity 77 may protect the lung from injury by controlling excess inflammation 4,5 . In this study, no difference 78 of ACE2 in the lung between COVID-19 patients and control groups has been found, indicating 79 that ACE2 inhibitors might not be an ideal therapy in the treatment for COVID-19 6 . On the other 80 hand, we found that the ACE2 was downregulated in the kidney and heart of COVID-19 patients 81 ( Figure 2C ), which might be associated with its catalytic activity in the local renin-angiotensin 82 system (RAS) in these two organs 7 . CLEC4M is a highly expressed dendritic cell (DC) specific 83 adhesion receptor in the liver, and it recognizes T cells to promote immune response 8 . CLEC4M 84 was found to be downregulated in the liver of COVID-19 patients in this study ( Figure 2C ). It has 85 been reported that the hepatocyte specific expression of CLEC4M could promote clearance of Von 86 Willebrand factor (vWF) in mouse model 9 , which might be associated with hypercoagulability. 87 CD209, in the same family with CLEC4M, however, showed no differential expression in neither 88 organ. CD209 and CLEC4M are all associated with HCV infection 10 . On the contrary, CTSL was 89 upregulated in the lung, spleen and renal medulla of COVID-19 patients, which has been reported 90 to promote the SARS-CoV-2 entry and its inhibitor could suppress virus entry effectively 11 . The 91 inhibitor of CTSL might be an effective drug for COVID-19 treatment. The above examples 92 indicate that our data might complement the protein interaction data. The proteins which interact 93 directly with virus could also be dysregulated at protein level, which might be potential targets for 94 treatments. 95 Other receptors 96 To search for other potential targets for COVID-19, we reviewed validated virus entry 97 associated receptors and proteases 12 and checked their abundance among the seven organs. 98 Intracellular cholesterol transporter 1 (NPC1) binds to the glycoprotein of Ebola and its inhibitor 99 has been recognized as a potential target for the treatment of Ebola 13 . NPC1 is significantly 100 upregulated in most organs of COVID-19 patients, including the lung, white pulp of spleen, heart 101 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint and thyroid ( Figure 2C ). Considering the critical need for lipid and its metabolism during viral 102 replication 14 , NPC1 might be a potential drug target for the COVID-19. The carcinoembryonic 103 antigen-related cell adhesion molecule 1 (CEACAM1), which is the major receptor for murine 104 coronavirus on its host cells 15 , was significantly upregulated in the lung, liver, kidney, and thyroid 105 ( Figure 2C ). Its dimerization with the immune checkpoint TIM3 would further suppress adaptive 106 immunity 16 , so the inhibitor of CEACAM1 might be a potential target for COVID-19 treatment. In 107 the hepatocytes, CEACAM1 could respond to insulin 17 , which may be associated with the 108 hyperglycemia in the COVID-19 patient. In summary, this study might indicate the SARS-CoV-2 109 infection or potential drug target by the differential expression across eight organs between 110 COVID-19 patients and the control group. Table S5 ). By matching the experiential FC with 115 the predicted activation state in upstream regulator analysis using Ingenuity Pathway Analysis 116 (IPA), we found ten transcription factors expressed with the same trend, including nine 117 upregulated proteins and one downregulated protein (SI Figure 1 , Table S5 ). 118 Among the ten upregulated TFs (SI Figure 1) , seven of them were involved in the 119 inflammatory response, such as the acute phase response and NF-κB signaling, reflecting the 120 extensive inflammatory infiltration in these tissues in COVID-19 patients. NF-κB subunit 2 121 (NFKB2) is expressed in various cell types and plays a key role in proinflammation 18 . It functions 122 mainly through Toll-like receptor signaling pathway 19 and NF-κB signaling pathway 20 . 123 Transcription factor p65 (RELA) is a proto-oncogene and also encodes an NF-κB subunit protein. The heterodimeric RELA-NFKB1 complex has been reported to be the most abundant form of 125 NF-κB, and plays a key role in immune, inflammatory and acute phase responses and affect cell 126 proliferation and apoptosis 21 . In this study, RELA was upregulated in the thyroid and NFKB2 was 127 elevated in the lung, kidney and thyroid (SI Figure 1) , indicating a strong immune reaction in 128 these three organs. CCAAT/enhancer-binding protein β (C/EBPB) is a transcription enhancing 129 protein, which plays an important role in liver regeneration 22 , immune and inflammatory 130 responses 22 . NF-IL6 is a member of the CCAAT/enhancer-binding protein (C/EBP) family and it 131 is essential to induce G-CSF in macrophages and fibroblasts 23 . Upregulation of C/EBPB was 132 detected in the lung, spleen, liver, heart and kidney (SI Figure 1) , indicating potential immune 133 dysregulation or liver damage. Signal transducer and activator of transcription 1 and 3 (STAT1/3) 134 encode proteins of the STAT protein family. STAT is regulated and controlled by some cytokines 135 and growth factors 24 and then transmit the signal to downstream pathways such as cell growth and 136 apoptosis 25,26 . STAT3 can contribute to the inflammation activation in tumors by NF-κB and IL-6-137 GP130-JAK pathways 27 . Upregulation of STAT3 was observed in the spleen, liver, heart and 138 kidney, while STAT1 was only observed to be upregulated in the kidney (SI Figure 1 ). This may 139 indicate potential dysregulation of immune state of COVID-19 patients. Transcription factor jun-B 140 (JUNB) is a proto-oncogene encoding a transcription factor protein. It belongs to activate protein 141 1 (AP-1), which is regulated by varied physiological or pathological stimuli, such as cytokines, 142 growth factors and infections 28 . It acts as a negative regulator of proliferation by modulating cell-143 cycle regulators 29 . Upregulation of JUNB was observed across over the lung, spleen, liver, heart, 144 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint kidney and thyroid based on our analysis. 145 Other transcription factors either reflect the tissue injury or hypoxia state in patients in this study. The RB transcriptional corepressor 1 (RB1) was upregulated in the liver and 147 kidney (SI Figure 1) , which may negatively modulate the cell cycle 30 and induce a higher degree 148 of mitochondria permeabilization and apoptosis 31 . The La-related protein 1 (LARP1) was 149 upregulated in the lung, spleen, liver, kidney and thyroid (SI Figure 1 ). LARP1 can regulate 150 mRNA translation and is associated with mTOR signaling 32 , and it has been reported to interact 151 with SARS-CoV-2 33 . The hypoxia-inducible factor 1-alpha (HIF1A) was upregulated in renal 152 cortex (SI Figure 1) and was also predicted active in the lung, liver, renal cortex and medulla by is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Cluster 3: Coagulation system 165 Blood coagulation occurred in most patients died from COVID-19 in our study with clotting 166 in lower extremity vein (Table S1 ), which resulted from the induced coagulation cascade and the 167 imbalance between coagulation, anticoagulation system and the impaired fibrinolytic system 36 . 168 The activities of inflammatory cells and cytokines following virus infection would result in 169 endothelial injury and the secretion of tissue factors, which could initiate the coagulation 170 cascade 37,38 . Tissue factor pathway inhibitor (TFPI) could inhibit the activated factor Xa (F10a), 171 tissue factor catalytic complex and then inhibit the subsequent coagulation cascade 39 . In COVID-172 19 patients, TFPI was upregulated in the white pulp of the spleen and liver (SI Figure 2) , which 173 may occur with coagulation. Meanwhile, some coagulation factors were dysregulated in COVID-174 19 patients. For example, coagulation factor XII (F12) was downregulated in the heart, renal 175 cortex and thyroid, coagulation factor XI (F11) was decreased in the lung, renal cortex and 176 medulla while plasma kallikrein (KLKB1) was decreased in the lung, renal cortex and thyroid (SI 177 Figure 2 ). F12 has been reported to be activated by KLKB1 and the activated F12 could catalyze 178 F11. The activated F11 could activate factor IX (F9), which will lead to thrombosis and the 179 formation of fibrin 40 . In COVID-19 patients, F12 was decreased in the heart, renal cortex and 180 thyroid. Coagulation factor XIIIa (F13a) is activated in the last step of coagulation, which would 181 induce hemostasis. In addition, it would stabilize the fibrin clot to avoid fibrinolysis 41 . It was 182 increased in the renal cortex and thyroid, which could contribute to the formation of blood 183 clotting. vWF is a glycoprotein, which could bind to the factor VIII (F8) and protect F8 from 184 degradation by Vitamin K-dependent protein C (PROC). Besides, it could mediate the platelet 185 aggregation following the vascular injury 42 . The VWF was increased in the white pulp of the 186 spleen and renal cortex, which indicates the high risk of thrombosis risk. In contrast, it was 187 decreased in the heart and lung of the COVID-19 patients Von Willebrand factor (VWF). 188 Fibrinogen alpha chain, gamma chain and beta chain (FGA, FGG and FGB), which could be 189 cleaved to fibrin and generate the blood clots 43 , were all increased in the lung and all decreased in 190 the thyroid, while FGA was only increased in the renal cortex (SI Figure 2) . The prothrombin (F2) 191 was decreased in the heart (SI Figure 2 ). 192 The Vitamin K-dependent protein S (PROS1) and PROC belong to the protein C 193 anticoagulant system. PROS1 is the cofactor of PROC, which could degrade factor VIIIa (F8a), 194 factor Va (F5a) and protease-activated receptor 1 (PAR-1) once activated 44 . Alpha-1-antitrypsin 195 (SERPINA1) is an inhibitor of PROC 45 . Plasma serine protease inhibitor (SERPINA5) is also a 196 serine proteinase inhibitor and acts as an inhibitor of protein C and other coagulation enzymes 46 . 197 In the COVID-19 patients, PROC was decreased in the heart and PROS1 was decreased in the 198 kidney (SI Figure 2) , which may contribute to the thrombosis. SERPINA1 is also decreased in the 199 heart and thyroid. SERPINA5 is decreased in the liver, heart, renal cortex and thyroid. 200 Antithrombin Ⅲ ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint heart, renal cortex, medulla and thyroid (SI Figure 2) , which could lead to the generation of 209 thrombin or the procoagulant state in the body. 210 In the fibrinolytic system, plasminogen (PLG), the zymogen, could convert into serine 211 proteinase plasmin by two serine peptidases, the tissue plasminogen activator (PLAT) and 212 urokinase plasminogen activator (uPA) 50 . Then the plasmin could breakdown the blood clotting. In 213 this study, PLG was downregulated in the heart and thyroid while PLTA was upregulated in the 214 liver of the COVID-19 patients (SI Figure 2) . Alpha-2-antiplasmin (SERPINF2) was 215 downregulated in the heart, renal medulla and thyroid of the COVID-19 patients (SI Figure 2) , 216 which may indicate the increased fibrinolysis 51 . Plasminogen activator inhibitor 1 (SERPINE1) is 217 a serine proteinase inhibitor and acts as a major inhibitor of plasminogen activators. In the 218 COVID-19 patients, SERPINE1 significantly upregulated in the lung, liver, heart, renal cortex and 219 medulla (SI Figure 2) , which could increase the risk of thrombosis and fibrosis 52 . Alpha-2-220 macroglobulin (A2M) could bind to varied proteinases, such as plasmin and kallikrein, and 221 inactive them. And in sepsis, it would decrease because of the formation of complex 53 . Here, we 222 found A2M was decreased in lung, heart, renal medulla and thyroid (SI Figure 2) . 223 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. Glucocorticoid receptor (NR3C1) was significantly downregulated in five organs (except for 247 testis and thyroid) in our study (SI Figure 3) . NR3C1 usually exists in the cytoplasm and would be 248 translocated to the nucleus after binding to its ligand. It could upregulate the anti-inflammatory 249 protein or inhibit the expression of pro-inflammatory protein in the nucleus 59 . The significant 250 downregulation of NR3C1 in the five organs may indicate an increased inflammatory response of 251 various organs after SARS-CoV-2 infection. 252 Our data indicated that interleukin-6 receptor subunit beta (IL6ST) was significantly 253 upregulated in COVID-19 patients' thyroid (SI Figure 3 ). IL6ST is involved in the signal 254 transduction of IL-6-type cytokines. After binding to its receptor, IL6ST is driven to form a 255 complex by IL6, then activating Janus kinases (JAKs) and STAT3 and participating in acute phase 256 response, T cell differentiation, antibody production and proliferation 60,61 . IL6 is a key pro-257 inflammatory factor in the early stage of infection and is associated with prognosis 60 . It has also 258 been reported to be overexpressed in the serum of severe COVID-19 patients 62 . 259 The abundance of angiopoietin like 6 (ANGPTL6) in the thyroid tissue of COVID-19 260 patients was significantly downregulated (SI Figure 3 ). ANGPTL6 plays a role in angiogenesis, 261 lipid metabolism and glucose metabolism 63 . It has been reported that in the ANGPTL6 deficient 262 mouse model, obesity, lipid accumulation and insulin resistance were developed. In contrast, the 263 mouse would be more sensitive to insulin by activating the ANGPTL6, which indicates that 264 ANGPTL6 is related to insulin resistance 64 . The downregulation of ANGPTL6 in the thyroid of 265 COVID-19 patients indicates a potential insulin resistance status in COVID-19 patients. 266 Our data showed that the expression of natriuretic peptides A (NPPA) in the heart tissue of 267 COVID-19 patients was significantly downregulated (SI Figure 3) . NPPA belongs to the 268 natriuretic peptide family, which regulates the extracellular electrolyte homeostasis. The cardiac 269 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint natriuretic peptide, also known as vasodilation, is mainly produced, stored, and secreted by atrial 270 cardiomyocytes. When the blood volume increases and the heart or blood vessel wall is stimulated 271 to release atrial natriuretic peptide by a large stretch which causes powerful natriuretic and diuretic 272 effects. The knockout of NPPA receptor (NPR1) in the heart of mice exhibited cardiac 273 hypertrophy 65 and the knockout of NPPA could cause heart failure and hypertension 66 . The 274 downregulation of NPPA implies potential heart damage in COVID-19 patients. 275 Downregulation of fibroblast growth factor 2 (FGF2) was detected in the liver of COVID-19 276 patients (SI Figure 3 ). FGF2 is a growth factor that belongs to the heparin-binding (fibroblast) 277 growth factor family. In the renal medulla of COVID-19 patients, IL13RA1 was significantly upregulated (SI 287 Figure 3 ). IL13RA1 is a subunit of the interleukin 13 receptor, which mainly mediates IL-4 signal 288 transduction. IL-4 and IL-13 both belongs to the profibrogenic cytokines 69 . It has been reported to 289 protect the lung from bleomycin induced injury 70 . 290 Interferon-gamma receptor 1 (IFNGR1) was overexpressed in multiple kinds of organs 291 except for the thyroid and testis (SI Figure 3 ). IFNGR1 is a ligand-binding chain of heterodimeric 292 gamma interferon receptors on macrophages and is a functional receptor for interferon-gamma 71 , 293 which triggers host immunity to virus infection 72 , such as induction of phagocyte oxidase system, 294 NO production and lysosomal enzymes for microbe destruction in macrophages 73 . The 295 overexpression status of IFNGR1 implies the systemic immune response activated by SARS-CoV-296 2. 297 Interleukin 1 receptor-like 1 (IL1RL1) was found to be upregulated in the kidney cortex of 298 COVID-19 patients in this study (SI Figure 3) . IL1RL1 belongs to the interleukin 1 receptor 299 family, which is a receptor for interleukin-33 (IL-33) 65 . IL-33 signal transduction could lead to the 300 activation of NF-κB, MAP kinase and induction of Th2 cytokines 66 . It has been reported that 301 IL1RL1 was overexpressed in aged SARS-CoV infected animals, and the overexpression of 302 IL1RL1 indicates that older macaques have a stronger host response upon viral infections than 303 young macaques 74 . This may indicate that a pro-inflammatory status in COVID-19 patients. 304 Eosinophil-derived neurotoxin (RNASE2) was found to be downregulated in the COVID-19 305 patient's kidney cortex (SI Figure 3) . RNASE2 is derived from eosinophils and has antiviral 306 activity and selective chemotactic properties to dendritic cells 75 . It can reduce the activity of 307 single-stranded RNA virus through ribonucleolytic enzyme activity and interaction with the 308 extracellular virus by its unique structure 76 . The downregulation of RNASE2 in the renal cortex 309 of COVID-19 patients may indicate dysregulation of the immune system or may be a result of 310 consuming itself to binding with and inhibit extracellular virus in COVID-19 patients. 311 Syndecan-4 (SDC4) was upregulated in the liver of the COVID-19 patients (SI Figure 3) . 312 SDC4 is a membrane proteoglycan. It can support exosome biogenesis and engagement of FGF 313 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint with its receptor, which plays a role in angiogenesis, inflammation and infection 77 . 314 C-X-C motif chemokine 13 (CXCL13) was observed to be upregulated in the spleen of 315 CVOID-19 patients (SI Figure 3 ). CXCL13 is a member of the CXC chemokine family, which 316 interacts with the chemokine receptor CXCR5 to selectively chemotactic for B cells 78 . 317 CXCL13/CXCR5 enhances antigen encounter and BCR-mediated B-cell activation through 318 regulation of actin cytoskeleton and activity of motor protein 79 . The upregulation of CXCL13 may 319 indicate the elevated humoral immune response in the spleen of COVID-19 patients. 320 Cathelicidin antimicrobial peptides (CAMP), an antimicrobial peptide family member, was 321 downregulated in the spleen of the COVID-19 patients (SI Figure 3) . When mammals encounter a 322 large number of bacterial invasions, it plays a role in the innate immune defense by inducing 323 leukocyte chemotaxis, degranulation, the response of macrophages and stimulating wound 324 healing 80 . The downregulation of CAMP may indicate the dysregulation of innate immunity in 325 COVID-19 patients. 326 Retinoic acid receptor RXR-alpha (RXRA) was detected to be downregulated in the lung of 327 the COVID-19 patients (SI Figure 3 ). RXRA is a nuclear receptor for retinoic acid 81 and regulates 328 lipid metabolism and inflammation in macrophages 82 . In response to viral infections, it plays a 329 role in weakening the innate immune system. It has been reported that the downregulation of 330 RXRA would induce the production of type I IFN and antiviral response 83 . Downregulation of 331 RXRA may indicate a proinflammatory state in the lung of COVID-19 patients. 332 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint walls for migration. Several protein fragments are produced by the digestion of the blood vessel 348 walls, which would intensify the proliferative and migratory activity of endothelial cells and then 349 form a capillary tube by altering the arrangement of their adherence membrane proteins, such as 350 vascular cell adhesion molecule (VCAM) and integrin 88 . Finally, new blood vessels become 351 mature and stabilized by Ang, PDGF (platelet derived growth factor) and transforming growth 352 factor beta (TGFB), resulting in a continuous blood flow 89 . 353 It is known that hyperbaric oxygen therapy increases the expression of HIF and actives 354 VEGF production 90 . Thereby, we can speculate that severe COVID patients with ARDS after 355 ventilator treatment would be pro-angiogenesis. However, the angiogenesis may not be specific to 356 COVID cases. Recently, a study which compared tissues from seven lung samples obtained from 357 patients who died from COVID-19, tissues from 7 lungs obtained from ARDS secondary to 358 influenza A(H1N1) infected corpses and tissues from 10 age-matched uninfected lungs found that 359 the amount of new vessel generated by intussusceptive angiogenesis was 2.7 times as high as that 360 in the lungs from patients with influenza 91 . These results support a more profound evidence of 361 pro-angiogenesis in COVID-19 patients. 362 It is worth noting that 139 proteins involved in seven organs are related to angiogenesis by 363 our proteomic data analysis. It implies that the angiogenesis process has differences between 364 COVID-19 patients and healthy controls. 365 As a supplement to that study, our multi-organ data found a multi-organ angiogenesis 366 process, not merely in the lung. The vascular endothelial growth factors A (VEGFA) was 367 upregulated in the thyroid, and the VCAM1 was upregulated in the kidney (cortex as well as 368 medulla) of COVID-19 (SI Figure 4) . The MMP protein 14 were found upregulated in the spleen, 369 lung and thyroid, and the MMP2 were induced in thyroid, lung and renal cortex in COVID-19 370 cases (SI Figure 4) . We also quantified transforming growth factor beta related proteins (TGFBI) 371 and angiogenin (ANG) in our proteomics data, while it was not upregulated in all of these COVID 372 organs (SI Figure 4) . 373 Besides the proteins that directly participate in angiogenesis, we also detected some potential 374 regulatory ones. Firstly, the upstream hypoxia inducible factor 1 subunit alpha (H1F1A) was 375 found to be increased in the kidney of COVID-19 cases, which actives VEGF production and 376 angiogenesis. In addition, the integrin proteins (ITGA5, ITGB1, and ITGB3) are found up-377 regulated in the lung, heart, liver or renal cortex (SI Figure 4) . Many molecules participate in the 378 processes of angiogenesis, endothelial cells proliferation and invasive signal. Integrins are the 379 principle adhesion receptors in forming extracellular microenvironment, and integrin-mediated 380 interactions mainly regulate cell proliferation, migration, and survival 92 . The chemokine CX3CL1 381 could induce the monocytes accumulation and angiogenesis during inflammation 93 . Our data also 382 found the overexpression of CX3CL1 in COVID-19 patients' thyroid (SI Figure 4) , which may 383 indicate the angiogenesis potential in thyroid. It is found that SERPIN family is anti-angiogenesis. 384 In the rat, blockage of SERPIN family would mediate the process of angiogenesis by interleukin 8 385 (IL-8) and VEGF. In assays of cellular events in angiogenesis, SERPIN family blocked the 386 processes of invasion, migration and tube formation 94 . Our results showed a downregulation 387 pattern of SERPIN family proteins in multiple organs of COVID-19 cases. The SERPINA1, 388 SERPINF1, and SERPING1 are significantly reduced in heart (SI Figure 4) . Besides, SERPINA1 389 was also found downregulated in the thyroid, and SERPING1 are found downregulated in the 390 renal medulla and liver (SI Figure 4) . Transmembrane Protein 100 (TEME100) is an intracellular 391 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint transmembrane protein. It is involved in the differentiation of arterial endothelium and vascular 392 morphogenesis, which can be activated by AKT1 receptor 95 . In addition, TEME100 plays a vital 393 role in maintaining vascular integrity and vascular genesis 96 . In our proteomic data, TEME100 394 were downregulated in the lung of COVID-19 patients (SI Figure 4) . It hints that the blood vessels 395 of the lung in COVID patients might have poor stability, resulting in increased risk of 396 angiogenesis in the lung under weak vascular integrity. 397 In conclusion, we suspected that the balance of angiogenesis is dysregulated in COVID-19 398 patients, which results in pathological angiogenesis and causes an increased blood-vessel 399 formation. 400 SI Figure is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint with Student's T test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. Cluster 6: Fibrosis 407 Fibrosis markers 408 The fibrosis process is associated with the overexpressed extracellular matrix, collagen 409 proteins and proliferation of fibroblasts 97 . COL1A1 and COL1A2 are pro-alpha1 and 2 chains of 410 type I collagen, and COL3A1 is collagen type III alpha 1 chain. All of them belong to fibril-411 forming collagens, which are produced by fibroblasts and act as the essential components of the 412 myocardial interstitial matrix. These three proteins were downregulated in heart tissue samples 413 from COVID-19 patients (SI Figure 5) and downregulated LAMB2 and LAMC1 in renal medulla (SI Figure 5) . It is reported that 424 increased matrix metalloproteinase 7 and 9 (MMP7 and MMP9) are closely related to the 425 development of fibrotic kidneys, and laminins are the substrate of MMP7 104 and MMP9 105 . 426 Although we didn't find significant upregulation of MMP7 and MMP9, the downregulation of 427 LAMB2 and LAMC1 may indirectly indicate renal fibrosis. 428 Matrix metalloproteinases (MMPs) and metalloproteinase inhibitors (TIMPs) maintain the 429 balance of fibrogenesis and fibrosis 106,107 . In our dataset, we identified MMP2, MMP9, MMP14, 430 IMMP2L, MMP28, TIMP1,2 and 3. They are all identified upregulated over the different organs 431 (SI Figure 5 ). Fibrosis in pathological was only found in the lung, in which two kinds of inhibitors 432 were upregulated. It might indicate a positive feedback loop between MMPs and TIMPs. 433 The pulmonary fibrosis, which is associated with fibrous exudation, hyaline membrane 434 formation and alveolar space collapsed. We have identified the upregulation of lung fibrosis 435 biomarkers including Chitinase-3-like protein 1 (CHI3L1) 108 and pulmonary surfactant associated 436 protein B (SFTPB) (SI Figure 5) . CHI3L1 was upregulated in the widest distributed among five 437 tissues including the lung, heart, liver, and kidney (SI Figure 5) . SFTPB promotes the secreted 438 alveolar surfactant and sustains alveolar structure 109 . The SFTPB was upregulated in the lung of 439 COVID-19 patients. FABP family is similar to the surfactant 110 . We found FABP3, FABP1 and 440 FABP5 were downregulated based in our dataset (SI Figure 5) . The downregulated FABPs 441 indicated the potential of fibrosis. 442 Lipid metabolism is also associated with fibrosis. The fibrosis influenced by lipid metabolism 443 is the transformation between lipofibroblast and myofibroblast. TGF-beta can induce 444 lipofibroblast differentiation to myofibroblast which is the process of fibrosis generation 111 . The 445 markers of lipofibroblast can be the potential markers for fibrosis, such as perilipin-2 (PLIN2). In 446 COVID-19 patients, PLIN2 upregulated in the lung, liver, heart, and spleen (SI Figure 5) . 447 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint and control groups was performed with Student's t Test. *, p < 0.05; **, p < 0.01; ***, p < 452 0.001; ****, p < 0.0001. Fibrosis associated proteins 455 Fibrosis could be divided into four stages 69 . At the initiation stage, the cell and organ damage 456 would initiate a cascade of stress and immune responses. In response to the initial stress, multiple 457 inflammatory signaling pathways were activated, such as the chemokine signaling, complement 458 system, macrophage activation, NF-κB signaling, interferon, platelet and neutrophil degranulation. 459 Thirdly, chronic inflammation would drive the differentiation or proliferation of fibroblasts and 460 wound-healing response. Fourthly, the extracellular matrix of immune cells and fibroblast cells 461 would be further modified. Here we compared the dysregulated proteins in our studies with 462 proteins in these pathways of the fibrosis and selected the top 20% dysregulated proteins with the 463 highest fold changes in a specific organ for discussion. 464 In COVID-19 patients, alcohol dehydrogenase 1B (ADH1B) was downregulated in the 466 lung and liver, while it was upregulated in the white pulp of spleen, heart and thyroid. Alcohol 467 dehydrogenase 6 (ADH6) was downregulated in the lung and renal cortex. Aldehyde 468 dehydrogenase family 3 member A2 (ALDH3A2) was downregulated of in the liver, heart, 469 and renal cortex. Alcohol dehydrogenase 1C (ADH1C) was downregulated in the liver. 470 Alcohol dehydrogenase 4 (ADH4) was downregulated in the liver while it was upregulated in 471 the heart (SI Figure 6 ). They all belong to the alcohol dehydrogenase family and are involved 472 in the metabolic process of multiple substrates, such as ethanol, hydroxysteroids, and lipid 473 peroxidation products. It has been reported that lipid metabolism dysregulation can induce is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Lysosomal acid lipase (LIPA) was upregulated in the heart of COVID-19 patients (SI Figure 496 6). It is located in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. 497 The deficiency of LIPA will lead to the accumulation of fat and cause cholesterol ester storage 498 disease (CESD). The accumulation of cholesteryl esters and triglycerides in hepatocytes result in 499 hepatomegaly with progressive fibrosis and liver cirrhosis 119 . Our data showed no significant 500 difference in LIPA expression in the liver but upregulation in the heart, which might indicate the 501 fibrosis initiation in the heart. 502 Phospholipid transfer protein (PLTP) was upregulated in the liver of COVID-19 patients (SI 503 Figure 6 ). It is responsible for lipid transfer and it can transfer phospholipids from triglyceride-504 rich lipoprotein to high-density lipoprotein (HDL) and regulate lipid metabolism 120 . The liver is 505 one of the main sites for the production and degradation of lipoprotein and the expression of 506 PLTP. Studies have shown that PLTP can amplify the pro-inflammatory effect of 507 lipopolysaccharide (LPS). In the mouse model, overexpression of PLTP can induce 508 atherosclerosis 121 . The overexpression of PLTP in COVID-19 liver tissue may be associated with 509 potential liver injury. 510 Acyl-CoA desaturase (SCD) was upregulated in the lung of COVID-19 patients (SI Figure 6 ). 511 It exists in the endoplasmic reticulum and is mainly involved in fatty acid biosynthesis. SCD is 512 involved in inflammation and stress regulation of different cell types, including adipocytes, 513 macrophages, endothelial cells, and muscle cells 122 . Upregulated SCD expression in the mouse 514 model promotes hepatic fibrosis through Wnt/β-catenin signal and the lipid metabolism 123 . Here, 515 the upregulated SCD in the lung tissue of COVID-19 patients may affect the pulmonary fibrosis 516 process by regulating metabolism reprogramming. 517 Protein transport protein Sec61 subunit beta (SEC61B) was upregulated in the lung, white 518 pulp of spleen and kidney of COVID-19 patients (SI Figure 6 ). It is one of the two subunits of 519 SEC61 complex which is the core component of the protein transport device in the endoplasmic 520 reticulum and is responsible for the transport of polypeptides across the endoplasmic reticulum. 521 SEC61B is associated with the cytosolic fibrosis through dysregulation of endoplasmic 522 reticulum 124 . The upregulated SEC61B might indicate the fibrosis initiation in multiple COVID-19 523 organs. 524 Transforming Growth Factor Beta Receptor 2 (TGFBR2) was downregulated in the lung, 525 while it was upregulated in the heart of COVID-19 patients (SI Figure 6) . It can form a 526 heterodimer with TGF-receptor type 1 and bind TGF to participate in the transcriptional 527 regulation of genes related to cell cycle, wound healing, immune suppression, and tumor 528 formation. TGF signaling mediates fibrosis after the inflammatory damage in the heart, kidney, 529 and intestines 125 . TGFBR2 is also a potential target for inhibition of pulmonary fibrosis 126 . 530 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint SI Figure 6| Expression of dysregulated proteins involved in initiation of fibrosis 532 process. The y-axis stands for the protein expression ratio by TMT-based quantitative proteomics. 533 Pair-wise comparison of each protein between COVID-19 patients and control groups was 534 performed with student's t test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. 535 536 Aldo-keto reductase family 1 member B10 (AKR1B10) was upregulated in the renal 538 cortex of COVID-19 patients (SI Figure 7) . It belongs to AKR family 1 subfamily B 539 (AKR1B) 127 . Recent studies have shown that AKR1B10 is secreted into the stroma from liver 540 cells by binding to heat shock protein 90 and maybe a useful serum biomarker for advanced 541 fibrosis in nonalcoholic steatohepatitis (NASH) 127,128 . The upregulation of AKR1B10 might 542 indicate the potential fibrosis in the renal cortex. 543 Delta-aminolevulinic acid dehydratase (ALAD) was downregulated in the lung, white 544 pulp of spleen, liver, renal cortex and thyroid of COVID-19 patients (SI Figure 7) . It is the 545 principal lead binding protein in erythrocytes, which carry over 99% of the lead in blood 129 . It 546 is involved in the biosynthesis of heme 130 . Heme is a functional group of many heme proteins, 547 including cytochromes and hemoglobin (Hb), so it is essential for many different cellular 548 processes 131 . Excess free heme has been shown to exacerbate the pathogenesis of various 549 inflammatory diseases, such as sepsis, malaria, sickle cell disease, kidney disease, and 550 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint multiple organ failure 131-134 . Chronic obstructive pulmonary disease (COPD) patients show 551 increased cell-free Hb, correlating with disease severity 135 . However, we identified ALAD 552 was significantly downregulated in the multiple organs of COVID-19 patients. 553 Apolipoprotein was downregulated in COVID-19 patients compared with non-COVID-19 554 controls, mainly in liver, heart, kidney and thyroid (SI Figure 7) . Based on the ability of 555 apolipoprotein to inhibit inflammation, oxidative stress, and tissue remodeling, as well as to 556 promote The reduction of ApoC-II based on our analysis further indicated the reduced metabolic level of 575 triglycerides-rich lipoproteins in patients with COVID-19 infection. 576 Antioxidant 1 (ATOX1) was downregulated in the white pulp of spleen, renal cortex and 577 thyroid of COVID-19 patients (SI Figure 7) . It plays a crucial role as a copper chaperone 143-145 . It 578 is worth mentioning that ATOX1 was found to have a pivotal role in inflammation via inhibition 579 of inflammatory responses. The decrease of ATOX1 suggested the occurrence of prophase 580 inflammation 145 , which might indicate an inflammation stage before fibrosis in these organs. 581 Complement component 3 (C3) was downregulated in the lung, heart and thyroid in COVID-582 19 patients, but it was upregulated in the white pulp of spleen (SI Figure 7) . The complement 583 system is a crucial part of the immune system that is involved in the pathogenesis of various 584 inflammatory lung conditions, including infectious disease and chronic obstructive pulmonary 585 disease 146-149 . Complement component 3 (C3) plays a central role in the activation of the 586 complement system 149-151 . Additionally, C3-targeted intervention may provide broader therapeutic 587 control of complement-mediated inflammatory damage in COVID-19 patients 152 . 588 Catalase (CAT) was downregulated in the lung, white pulp of spleen, liver and renal 589 cortex of COVID-19 patients (SI Figure 7) . It is an important antioxidant enzyme in the 590 process of defense against oxidative stress 153 . It is preferentially expressed in the alveolar 591 epithelial cells. The downregulated CAT has been reported in the fibrotic lungs of human, 592 which may be associated with the protective role of CAT against inflammation and 593 subsequent fibrosis associated processes, such as TGF-β expression and collagen content 154 . 594 The downregulated CAT may trigger the proinflammation state and contribute to the fibrosis 595 process in these organs. 596 Monocyte differentiation antigen (CD14) was upregulated in the white pulp of spleen and 597 renal cortex of COVID-19 patients (SI Figure 7) . It is a surface antigen and preferentially 598 expressed on monocytes or macrophages, which plays multiple pivotal biological roles, such as 599 innate immune response to binding bacterial lipopolysaccharide 155 . Additionally, it has been found 600 that CD14 was highly expressed in the lung, liver, spleen, and its expression was dynamically 601 changed in the course of inflammation 156 . Another study showed that systematic inhibition of 602 CD14 could reduce organ inflammation, which was tested in lung, liver, spleen, and kidneys. 603 They also reported that ICAM-1 and VCAM-1 were significantly inhibited in the kidneys by 604 inhibiting CD14 157 . 605 Chitinase-3-like protein 1 (CHI3L1) was upregulated in the lung, liver, heart, renal 606 cortex and medulla of COVID-19 patients (SI Figure 7) . It is a member of chitinase family 158 607 and is highly expressed in the liver 159 . In arthritic articular cartilage, CHI3L1 functions as a 608 growth-factor for fibroblasts 160 . In the bleomycin-treated mice, it would decrease transiently 609 due to its protective role in the injury. Then it would increase and play a profibrotic role in 610 activating macrophages and inducing the fibroblast and matrix deposition 108 . The upregulated 611 CHI3L1 in multiple organs of COVID-19 patients may indicate a profibrotic state. 612 C-reactive protein (CRP) was upregulated in six organs (except testis) of COVID-19 613 patients (SI Figure 7) . Fibrosis is caused by scar tissue formation in internal organs. Two 614 closely related human serum proteins, serum amyloid P (SAP), and C-reactive protein (CRP), 615 strongly affect fibrosis 161 . In multiple animal models, and even Phase 1 and Phase 2 clinical 616 trials, CRP indicates the potential of fibrosis 162,163 . It's worth noting that CRP was significantly 617 upregulated in almost all of organs based on our analysis. This prompts us that the follow of 618 CRP levels could potentially indicate the fibrogenesis status of COVID-19 patients. 619 FGB and FGG were upregulated in the lung but downregulated in the thyroid of 620 COVID-19 patients (SI Figure 7) . They are both blood-borne glycoproteins and components 621 of fibrinogen, which play a role in vascular injury and dysregulated in thrombophilia 164 , as 622 well as a proinflammatory role under several pathologic conditions including pulmonary and 623 kidney fibrosis 165 . Fibrinogen was substantially higher in COVID-19 patients than those in 624 healthy controls 166 . Meanwhile, in the process of acute phase response, interleukin-6 (IL-6) 625 could induce upregulation of the three fibrinogens, FGA, FGB and FGG, in liver and lung 626 epithelium 167 . Consistent with fibrosis observed in the lung of COVID-19, FGB and FGG 627 were evaluated in lung but decreased in thyroid. 628 Glutathione Peroxidase 2 (GPX2) was found to be elevated in the liver of COVID-19 629 patients (SI Figure 7) . GPX2 is a glutathione peroxidase, which catalyzes the reduction of 630 hydrogen peroxide (H2O2) by glutathione. Oxidative stress initiates epithelial cell injury and 631 fibrogenesis. Hence decreasing of glutathione results in hepatic fibrosis 168 and pulmonary 632 fibrosis 169 . Elevated GPX2 in the liver predicts fibrogenesis in the liver of COVID-19 patients. 633 Intercellular adhesion molecule (ICAM)-1 was upregulated in the spleen, liver, heart, kidney 634 and thyroid of COVID-19 patients (SI Figure 7) . ICAM1 is a member of the immunoglobulin 635 (Ig) superfamily expressed on fibroblasts and epithelial cells. ICAM deficiency suppresses 636 cytokine production, white cell infiltration and attenuates fibrogenesis 170 . The upregulation of 637 ICAM1 indicates the occurrence of inflammation and fibrosis. 638 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Protein tyrosine phosphatase non-receptor type 1 (PTPN1) was upregulated in five organs 639 (except the heart and testis) of COVID-19 patients (SI Figure 7) . It is the founding member of 640 the protein tyrosine phosphatase (PTP) family. PTP1B was upregulated in the fibrotic liver, which 641 may be induced by TGF-β1 171 . Based on our analysis, the elevated level of PTPN1 can be 642 observed in the lung, spleen, liver, kidney and thyroid, indicating a potential fibrosis status in 643 these organs. 644 Serum Amyloid A1(SAA1) was found to be significantly upregulated in the lung, liver, heart 645 and kidney of COVID-19 patients (SI Figure 7) . SAA1 is a major acute phase protein that is 646 highly expressed in response to inflammation and tissue injury 172 . Significant upregulation of 647 SAA1 may indicate an inflammation status in these organs, which may contribute to fibrosis in the 648 end. 649 Superoxide dismutase 1(SOD1) was found to be down-regulated in the spleen, heart, kidney 650 and thyroid of COVID-19 patients (SI Figure 7) . SOD1, a copper and zinc binding protein is an 651 enzyme for cleaning free superoxide radicals. Superoxide dismutase can act as a potential anti-652 fibrotic drug for Hepatitis C related fibrosis 173 . In our proteomics data, the downregulation of 653 SOD1 indicates a potential fibrosis status in these organs. 654 Vascular cell adhesion molecule 1(VCAM1) was upregulated in the kidney of COVID-19 655 patients (SI Figure 7) . It is a cell surface sialoglycoprotein expressed by cytokine-activated 656 endothelium. VCAM1 is upregulated in IPF, which is responsive to TGF-β1 174 . The upregulation 657 of VCAM1 in the kidney may indicate the fibrosis potential in COVID-19. 658 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint process. The y-axis stands for the protein expression ratio by TMT-based quantitative proteomics. 661 Pair-wise comparison of each protein between COVID-19 patients and control groups was 662 performed with student's t test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. 663 664 β-arrestin1 (ARRB1) was downregulated in the lung, white pulp of spleen, liver and renal 666 medulla of COVID-19 patients (SI Figure 8) . It has been demonstrated to function as a 667 molecular scaffold that regulates cellular function by interacting with other partner proteins, and 668 involved in multiple physiological processes including immune response, tumorigenesis and 669 inflammation 175 . The β-arrestins are universally expressed, but the neural and immune systems 670 have a much higher expression level. Previous studies have reported that ARRB1 specifically 671 regulates the survival and homeostasis of CD4+ T cells and thus affects the adaptive immune 672 responses 176 . The downregulation of ARRB1 in lung, spleen, liver and kidney in COVID-19 673 patients further suggests an end-stage immune response in COVID-19 patients. In addition, 674 ARRB1 has been reported to stimulate several signaling pathways involved in fibrosis, such as 675 TGF-β pathway. These pathways would affect cell growth, extracellular matrix deposition and 676 activation of inflammation 177 . The dysregulated ARRB1 may participate in the fibrosis process in 677 COVID-19. 678 Cadherin 2 (CDH2) was downregulated in the renal cortex of COVID-19 patients (SI Figure 679 8). It can mediate the adhesion between homotypic cells by binding to the CDH2 chain on another 680 cell's membrane. In the process of IPF, CDH2 was transformed into CDH11, leading to the 681 aggravation of pulmonary fibrosis 178 . Our data show that the expression of CDH2 in the kidney of 682 COVID-19 patients is decreased. However, the reduction of CDH2 in the renal cortex may be due 683 to the conversion of CDH2 to CDH11, which needs further investigation. 684 Stromal cell-derived factor 1 (CXCL12) was upregulated in the thyroid of COVID-19 685 patients (SI Figure 8) . It has been reported as a pre-B cell growth factor and would contribute to 686 lymphopoiesis and embryogenesis homeostatic processes via regulating the migration of cells 179 . 687 Moreover, exogenous CXCL12 would promote the migration and proliferation of human lung 688 fibroblasts and CXCR4/CXCL12 plays an important role in IPF 180 . The upregulated CXCL12 in 689 the thyroid may be an underlying factor for fibrosis. 690 Hypoxia-inducible factor-1 (HIF-1) was upregulated in the renal cortex of COVID-19 691 patients (SI Figure 8 ). It regulates genes and processes in response to hypoxia. It was upregulated 692 in chronic kidney disease and could promote fibrogenesis 181 . The upregulated HIF1A protein in 693 COVID-19 patients may be an early fibrosis maker. 694 Insulin receptor (INSR) was upregulated in the white pulp of spleen, liver and thyroid of 695 COVID-19 patients (SI Figure 8 ). It binds with insulin or other ligands to activate the insulin 696 signaling pathway. In C57BL/6 mice, when insulin receptor (InsR) are haploinsufficient, the mice 697 showed impaired hepatic insulin signaling and promoted liver fibrosis accumulation, which 698 correlated with the induction of matrix stabilization protein Lysyl oxidase like 2 (Loxl2) 182 . The 699 upregulated INSR may indicate the activated insulin signal and a more stabilized matrix. 700 Integrin alpha-1(ITGA1) was downregulated in the lung of COVID-19 patients (SI Figure 701 8). It belongs to a subunit of integrin protein family. Together with the beta 1 subunit, ITGA1 is 702 the receptor for laminin and collagen. Integrins are involved in communicating with the 703 extracellular matrix, inflammatory cells, fibroblasts and parenchymal cells. Hence, they are 704 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint intimately involved in the processes of initiation and maintenance and resolution of tissue fibrosis. 705 Fibrosis models of multiple organs have demonstrated that integrins have profound effects in 706 fibrotic process. It is now known that integrins modulate the fibrotic process through activating 707 TGF-β 183 . Our results found a declined ITGA1 in the lung, suggesting a potential downregulated 708 activity of integrin in the lung. 709 Methyl-CpG-binding protein 2 (MECP2) was downregulated in the lung and liver of 710 COVID-19 patients (SI Figure 8 ). It is expressed by hepatic stellate cells (HSCs) and involves in 711 the liver fibrosis in mice by silencing the peroxisome proliferator-activated receptor gamma 712 (PPARgamma) 184 . However, our data found downregulation of MECP2 in the liver. 713 Periostin (POSTN) was downregulated in the liver and heart of COVID-19 patients (SI 714 Figure 8 ). It is a secreted protein that exists in the extracellular matrix and could promote tissue 715 remodeling 185 . Overexpression of POSTN was reported in the lungs of patients with IPF and 716 deficiency of POSTN would protect the lung from fibrogenesis induced by bleomycin 186 . It was 717 upregulated after stimulation by TGF-β and would promote extracellular matrix deposition and 718 mesenchymal cell proliferation. The dysregulated POSTN may participate in the fibrosis process 719 in COVID-19. 720 Protein S100-A4 (S100A4) was downregulated in the spleen of COVID-19 patients (SI 721 Figure 8 ). It is a fibroblast specific protein and contains two EF-hand calcium-binding domains, 722 belonging to the S100 family of calcium-binding proteins. It has been studied in many kinds of 723 fibrosis 187 . 724 Plasminogen activator inhibitor 1 (SERPINE1) was upregulated in the lung, liver, heart renal 725 cortex and medulla of COVID-19 patients (SI Figure 8) . It inhibits the activities of urokinase-726 type/tissue-type plasminogen activator (uPA/PLTA), plasmin and plasmin-dependent MMP 188 , 727 which are all involved in the proteolytic degradation. In the fibrosis tissue, SERPINE1 is 728 significantly upregulated. Based on our analysis, elevated SERPINE1 may indicate a potential 729 fibrinolysis inhibition in these organs and result in fibrosis. 730 Signal transducer and activator of transcription 3 (STAT3) was upregulated in the white pulp 731 of spleen, liver, heart and renal cortex of COVID-19 patients (SI Figure 8) . It is an important 732 regulator of inflammation which is the primary step of fibrosis. It is activated in the inflammatory 733 stage of tissue fibrosis and promotes fibrosis by inducing ECM 189 . Based on our analysis, 734 overexpression of STAT3 may induce fibrosis in COVID-19 patients. 735 Thrombospondin 1(THBS1) was upregulated in the liver, heart and kidney of COVID-19 736 patients (SI Figure 8 ). It is a glycoprotein that is released by platelet α-granules and mediates cell-737 to-cell and cell-to-matrix interactions. THBS1 involves the fibrosis in TGF-β-dependent or -738 independent mechanisms and its antagonist could reduce the fibrosis 190 . The elevated level of 739 THBS1 in the liver, heart and kidney may suggest potential fibrosis in COVID-19 patients. 740 Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta (YWHAB) 741 was downregulated in the white pulp of spleen, heart and renal cortex of COVID-19 patients (SI 742 Figure 8 ). It is a member of the 14-3-3 protein family, which mediates signal transduction by 743 binding to phosphoserine protein and participates in metabolism, apoptosis and cell cycle 744 regulation 191 . 745 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint BCL2 associated X (BAX) was downregulated in the white pulp of spleen, heart, renal 765 medulla and thyroid of COVID-19 patients (SI Figure 9 ). It is a member of BCL2 apoptosis 766 regulatory protein family. It can promote the release of Cytochrome C, the activation of caspase-3, 767 and then apoptosis. TGF-β induced inflammation and fibrosis is BAX dependent and null 768 mutation of BAX can influence the TGF-β stimulated TIMP and MMP expression 194 . 769 Fibrosis is the accumulation of ECM components, or simply called collagen, in given 770 tissues 195 . Four types of collagens were dysregulated in COVID-19 patients (SI Figure 9 ). 771 Collagen alpha-1(I) chain (COL1A1) was downregulated in the heart. It was identified as a 772 potential biomarker for heart failure progression, and its upregulation was related to the 773 percentage of heart fibrosis 196 . The downregulation of COL1A1 may be associated with 774 myocardial hypertrophy in control groups. Collagen alpha-1(IV) chain (COL4A1) was found 775 upregulated in the spleen of COVID-19 patients. COL5A1 was found upregulated in the liver and 776 heart of COVID-19 patients (SI Figure 9 ). COLV is a minor component of the total hepatic 777 collagen (10-16%), but it could proliferate rapidly in active fibrogenesis in response to liver 778 injury 197 . COLV binds TGF-β1 in the ECM, thus controlling the availability of the pro-fibrotic 779 cytokine, which mediates fibrogenesis of neighboring cells. TGF-β1 could stimulate COL5A1 780 mRNA expression in mouse HSC culture, which is followed by deposition of COLV in the culture 781 matrix with resultant COLI and III fibrillar assembly in the matrix 198 . The upregulated COL5A1 782 may suggest damage and fibrogenesis in the liver and heart. COL6A3 was found upregulated in 783 the spleen and downregulated in the liver, heart and kidney of COVID-19 patients (SI Figure 9 ). 784 COL6, along with its derivatives are well-known biomarkers for hepatic fibrosis 199,200 . 785 Cathepsin L (CTSL) was upregulated in the lung, white pulp of spleen and thyroid of 786 COVID-19 patients (SI Figure 9 ). Cathepsin D (CTSD) was observed upregulated in the lung, 787 liver, heart and thyroid of COVID-19 patients (SI Figure 9 ). Cathepsin is a lysosomal cysteine 788 proteinase that participates in a role of intracellular protein catabolism and has been implicated in 789 myofibril necrosis in myopathies and myocardial ischemia, and the renal tubular response to 790 proteinuria 201 . CTSL was reported as a potential fibrosis marker in the liver, which would regulate 791 the extracellular matrix degradation and tissue remodeling 202 . Hepatic stellate cells (HSCs) are 792 responsible for extensive synthesis and deposition of ECM during liver fibrosis. CTSD has 793 important functions outside lysosomes including degradation of ECM components when secreted 794 to the extracellular space 203 . CTSD was observed upregulated during the activation of rat HSCs 795 and liver fibrogenesis 204 . It was reported that CTSD can drive HSCs proliferation and promote 796 their fibrosis potential in an in vivo mice model 205 . The upregulated CTSD in COVID-19 patients 797 may indicate the fibrosis process. 798 Tumor necrosis factor receptor superfamily member 6 (FAS) was upregulated in the lung, 799 white pulp of spleen and thyroid of COVID-19 patients (SI Figure 9 ). It is a key member of the 800 TNF-receptor superfamily as a receptor of TNFSF6/FASLG 206 . It has been reported that it played 801 a central role in the programmed cell death, and has been implicated in the diseases of immune 802 system leading to inflammation 207 . The elevated FAS was known in cystic fibrosis lungs 208 as 803 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint well induced inflammation and fibrosis in the liver by Hepatitis C virus 209 . The increased FAS 804 may indicate inflammation and fibrosis in fatal patients. 805 Kallikrein B (KLKB1) was downregulated in the lung, renal cortex and thyroid of COVID-19 806 patients (SI Figure 9 ). It is a plasma glycoprotein that participates in the surface-dependent 807 activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The plasma 808 kallikrein has been reported to activate the TGF-β1 signaling by depredating the latency-809 associated protein and is associated with liver fibrosis in patients 210 . The declined KLKB1 may be 810 associated with dysregulated blood coagulation. 811 The transcription factor farnesoid X receptor (NR1H4) was upregulated in the renal cortex of 812 COVID-19 patients (SI Figure 9 ). It is ligand-activated and highly expressed in liver, kidney, 813 intestine and adrenal glands. NR1H4 can reduce liver cell damage and fibrosis by upregulating 814 small heterodimer companion (SHP), thereby inhibiting the production of Type I collagen and 815 TGF-β signaling 211 . The elevated expression of NR1H4 in COVID-19 patients may participate in 816 the fibrosis process. 817 Plasminogen (PLG) was downregulated in the heart and thyroid of COVID-19 patients (SI 818 Figure 9 ). Its main function is to degrade fibrin clots then bind and activate on fibrin clots. The 819 function of plasminogen activator inhibitor type-1 (PAI-1) is to regulate micro-environmental 820 homeostasis and wound healing by inhibiting plasmin-mediated MMP activation 212 . Plasminogen 821 is dramatically increased in adults with ARDS. It is reported that additional plasminogen may be 822 effective in the treatment of lung lesions and hypoxemia during COVID-19 infections 213 . 823 Prostaglandin-endoperoxide synthase 2(PTGS2) was upregulated in the liver of COVID-19 824 patients (SI Figure 9 ). It converts arachidonate to prostaglandin H2 (PGH2), a fundamental step in 825 prostanoid synthesis 214,215 . Upregulation of PTGS2 results in an increased level of COX-2, which 826 potentially reduces Th2 immune responses and promotes neutrophil recruitment in hepatic 827 ischemia/reperfusion injury 216 . The injury may be related to fibrogenesis 217 . PTGS2 is 828 overexpressed in the bleomycin-induced pulmonary fibrosis, which was MMP-19 dependent 218 . 829 The elevated PTGS2 may indicate that COVID-19 patients are suffering from liver fibrogenesis 830 by the activated immune system. 831 Metallopeptidase inhibitor 1(TIMP1) was upregulated in the lung, liver, renal medulla and 832 thyroid of COVID-19 patients (SI Figure 9 ). It is a natural inhibitor of the matrix 833 metalloproteinases. TIMP-1 is related to the deposition of ECM, leading to fibrosis, which is 834 elevated in the profibrotic environments 219 . While there is no difference in fibrosis severity 835 between wild type and Timp1 -/mice, which may be due to the inhibition of inflammation by 836 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint TIMP1. The upregulated TIMP1 may be due to the fibrosis generation in these organs. 837 SI Figure 9| Expression of dysregulated proteins involved in modification of fibrosis 839 process. The y-axis stands for the protein expression ratio by TMT-based quantitative proteomics. 840 Pair-wise comparison of each protein between COVID-19 patients and control groups was 841 performed with student's t test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. 842 843 844 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Multi-organs proteomic changes (supple for Figures 6 and 7) 845 Lung and spleen 846 The lung is the primary and the only positive organ of virus infection (Table S1 ). To 847 investigate the virus induced pathological features, we first focused on the lung proteome. The 848 most significant pathologic injury in the lung of COVID-19 patients is fibrosis, accompanying 849 with fibrosis associated fibrous exudation, hyaline membrane formation and alveolar space 850 collapsed 220 ( Figure S1 ). 851 As discussed above (Cluster1: Receptor), the expression of ACE2, the known receptor of 852 SARS-CoV-2, and the expression of CD209 and CLEC4M, two receptors of SARS, shown no 853 significant changes in COVID-19 patients ( Figure 2C ). However, a couple of proteins acting as 854 the cellular entry of other viruses, such as CTSL, CEACAM1 and NPC1, were found upregulated 855 in the COVID-19 patients ( Figure 2C ). 856 During virus replication, double-stranded RNA (dsRNA) and uncapped mRNA of virus, 857 known as viral pathogen-associated molecular patterns (PAMPs), could trigger the innate immune 858 response once recognized by the pattern recognition receptors (PRRs) in the cytoplasm 221 . 859 According to the PRRs list 221 , we found CGAS was upregulated in the lung of COVID-19 patients 860 ( Figure 5A, SI Figure 10a ). The upregulation of CGAS further induces downstream response 861 including Type I interferon secretion and the release of several other cytokines 222 . 862 During the transcription and replication of coronavirus, host gene expression could be 863 blocked by mRNA suppression and translation shutoff. For example, the N protein has been 864 adapted to protect viral mRNA from degradation 223 . The lung is the only organ where SARS-CoV-865 2 viral RNA was tested to be positive in our study. Therefore, we compared the virus associated 866 pathways in the lung with the ones in other organs ( Figure 4C ). The trend of EIF2 signaling and 867 tRNA charging showed a similar trend in the lung and liver ( Figure 4A ). We found an inhibition of 868 ARE-mediated mRNA degradation pathway in the lung and an activation trend in all the other 869 organs ( Figure 4C ). Eukaryotic translation initiation factor 4E (EIF4E) as the cap-binding protein 870 in the host cell only increased in the lung of COVID-19 patients ( Figure 5A , SI Figure 10a ), which 871 could be a potential target for human coronavirus 229E (HCoV-229E) 224 . 872 Once virus infected the host, viral pathogen-associated molecular patterns (PAMPs), such as 873 dsRNA, would trigger host immune cells for defense. The major pathology in immune is hyper 874 inflammation, such as C-reactive protein (CRP) increasing and lymphopenia in the peripheral 875 blood and spleen of these patients ( Figures S1,2) . The white pulp of spleen consists of T and B 876 lymphocytes while the marginal zone of white pulp and red pulp contains the APCs. 877 Pathologically, we observed that white pulp was atrophic while no pathological changes were 878 observed in the red pulp (Figure 1 ), the latter of which is consistent with our proteome data (Table 879 S4). 880 In the lung of COVID-19 patients, high affinity immunoglobulin gamma Fc receptor Ⅰ 881 (FCGR1A) and low affinity immunoglobulin gamma Fc receptor Ⅱ-a (FCGR2A) was upregulated 882 ( Figure 5A ). While in the spleen, high affinity immunoglobulin epsilon receptor subunit gamma 883 (FCER1G), FCGR1A and FCGR2A were all upregulated ( Figure 5A ). These receptors expressed 884 on the monocytes surface for antigen presentation. TNF receptor-associated factor 6 (TRAF6) was 885 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint upregulated in the spleen of COVID-19 patients, which plays a role in dendritic cell maturation 886 and stimulation of naïve T cell 225 . TYRO protein tyrosine kinase-binding protein (TYROBP) was 887 upregulated in the lung and spleen of COVID-19 patients, which is involved in NK cell anti-viral 888 function and inflammatory reactions 226 . All these proteins participating innate cell activity indicate 889 the activated antigen presenting process or anti-viral functions. 890 The activation of NK cells might also be negative feedback for the decreasing T-, B-891 lymphocytes. Consistently, the adaptive immune associated pathways including B cell receptors 892 signaling, NFAT in regulation of the immune response were all inhibited (SI Figure 10b) . 893 Tyrosine-protein kinase (LCK), which actives CD8 T cell combined with LR2R 227 , was 894 downregulated ( Figure 5A ). CEACAM1 as a negative regulator of adaptive immune also 895 upregulated ( Figure 5A ) which indicated the immunosuppression state in the COVID-19 patients 896 and might strengthen the proinflammatory cytokine secreted. 897 Except for the above proteins, a well-known immunosuppression molecular, CD274 (PD-L1), 898 is upregulated significantly ( Figure 5A ) and PD-1, PD-L1 pathway was activated (SI figure 10c) 899 in the spleen of COVID-19 patients. When mapping our data with an immune checkpoint database 900 including 21 immune checkpoint proteins 228 , we found three dysregulated proteins, including 901 CEACAM1, CD276 and CD274 ( Figure 5A ). Upregulation CEACAM1 and CD276 appeared in 902 the lung and upregulation of CD274 was in the spleen. The upregulation of these checkpoint 903 proteins may indicate the suppression of adaptive immune function. 904 The proinflammatory state including the excess cytokines would induce tissue injury. M2 905 macrophages mainly participate in the wound healing and tissue repair process. Sterol 26-906 hydroxylase (CYP27A1) was upregulated in the COVID-19 patients ( Figure 5A ), which promotes 907 M2 conversion through increasing 27HC synthesis 229 . In addition, the maker of M2, CD163, was 908 upregulated in six organs (except testis), indicating that the wound healing and tissue repair have 909 been induced in the COVID-19 patients. Due to the excess export of lymphocytes to other injury 910 organs and increased apoptosis, exhausted lymphocytes and the white pulp may atrophy 230 . 911 In summary, these dysregulated proteins and enriched pathways suggest that the innate 912 immune was activated, the APCs were activated and increased with simultaneous wound healing, 913 while the adaptive immune was inhibited, which indicates the hyper inflammation state in the 914 COVID-19. To further validate the immune state in COVID-19, we performed the 915 immunohistochemical (IHC) staining for immune cells in the spleen and found that total T cell 916 (CD3), T helper cells (CD4), cytotoxicity T cells (CD8), and B cells (CD20) all decreased in the 917 spleen ( Figure S6 ). On the contrary, macrophage (CD68), especially M2 (CD163) all increased 918 ( Figure S6 ). These hyper inflammation state might further induce tissue over-repair and fibrosis. 919 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint 920 SI Figure 10| Characteristic proteins in lung and spleen of COVID-19 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint Liver 933 In the COVID-19 group, the main pathological changes in the liver are the steatosis and 934 coagulative necrosis ( Figure S1 ). Pathway analysis of 1,969 significant dysregulated proteins in 935 the liver shown the acute phase response signaling, eIF2 signaling, fatty acid α and β-oxidation, 936 necroptosis signaling pathway, apoptosis signaling and stearate biosynthesis were activated while 937 the xenobiotic metabolism was inhibited (SI Figure 11a) . Several key proteins related to 938 necroptosis were shown in SI Figure 11b . The steatosis and necrosis processes are always 939 accompanied by inflammation 231,232 . Thereby, we mapped our differentially expressed proteins in 940 the liver with the immunological proteins from GSEA-immunologic gene sets and then employed 941 IPA for pathway analysis for the overlapping proteins (SI Figure 11c) . The key proteins 942 participating in these pathways are shown in Figure 5B . The proinflammatory state in the liver 943 was reflected with activated IL-6, IL-8 signaling and NF-κB signaling. Remarkably, we found that 944 hepatic fibrosis signaling (SI Figure 11c ) was activated and hepatic fibrosis markers including 945 metalloproteinase inhibitor 1 (TIMP1) and plasminogen activator inhibitor 1 (SERPINE1) 233 were 946 upregulated (SI Figure 11b ). These dysregulated proteins might indicate that the chronic 947 inflammation and fibrosis process have initiated at molecular level though no obvious pathological 948 changes were observed. This phenomenon might be clinically meaningful for patients who have 949 recovered to take special care for the potential to develop fibrosis. 950 We hence propose a hypothetical model in the liver of COVID-19 patients according to the 951 main pathological changes and the enriched pathways (SI Figure 11d) . Firstly, the inflammation 952 biomarkers, such as C reactive protein (CRP), serum ferritin, IL-6 were significantly elevated in 953 COVID-19 patients ( Figure S2 ), which might be stimulated by the inflammatory response derived 954 from the lung through cytokines and immune cells. The upstream regulator, STAT3, and pathway 955 analysis, NF-κB signaling pathways were enriched, which were induced by cycling IL-1, IL-6 and 956 IL-8. As a result, the acute phase response was activated and the expression of CRP 957 upregulated 234 . Due to the activated NF-κB signaling, the two related catalytic subunits of IKK 958 kinase complex and its regulatory subunit, IKBKG, NEMO and IKKG, were all upregulated. The 959 IKK kinase complex induced the degradation of IκB inhibitory molecules and lead to the nuclear 960 translocation of the NF-κB dimers, which would activate transcription of genes participating in the 961 immune and inflammatory response 235 . Besides, the NF-κB could also activate IL-8 signaling and 962 TNF signaling, which may contribute to hepatic fibrosis process 236,237 . 963 Secondly, among the significantly dysregulated transcription factors (Table S5) , we noticed 964 the downregulated hepatocyte nuclear factor 4-alpha (HNF4A) (SI Figure 11b) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint the lung, as well as the drug-induced hepatotoxicity during therapy (SI Figure 11d) . 993 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint kidney injury 273 (Table S1) . 1105 In conclusion, renal tissue damage is more severe in renal cortex than in the medulla of 1106 COVID-19 patients, and the AKI may be caused by the combinational effects of hypoxia, bacterial 1107 infection, sepsis induced cytokine storm and drug-induced nephrotoxicity. 1108 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. In our study, 1,297 proteins in the thyroid were dysregulated (( Figure 1 ) and the top ten pathways 1120 are enriched for these proteins (SI Figure 14a ). 1121 Among these enriched pathways, eIF2 and mTOR upregulation might be associated with 1122 protein synthesis and indicate the dysregulation of thyroid function at molecular level. IL-8 and 1123 NF-κB signaling are associated with inflammatory response physically. The pathology associated 1124 pathways including angiogenesis (VEGF signaling), coagulation and thrombin signaling, cardiac 1125 hypertrophy signaling and renin-angiotensin signaling were also enriched (SI Figure 14A ). The 1126 key dysregulated proteins in these pathways are listed in the Figure S7D . We proposed a 1127 hypothetical model for thyroid pathology by these key proteins and pathways (SI Figure 14B ). 1128 The thyroid is adjacent to the superior respiratory system, thereby would be easily influenced by 1129 the inflammation. Some cytokines and their receptors, such as CXCL12, IL1R1 and IL6ST, were 1130 dysregulated, which could stimulate the NF-κB or mTOR signaling and then induce a series of 1131 downstream cascade reactions. CXCL12 is involved in promoting cell growth and angiogenesis 274 , 1132 which is associated with mTOR signaling 275 . In thyroid of COVID-19 patients, mTOR and 1133 CXCL12 were both upregulated ( Figure S7D ). IL-1 and IL-6 are associated with a variety of 1134 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint chronic inflammatory response, such as coagulation 276 and insulin resistance 277 , through 1135 activating NF-κB signaling. 1136 In the thyroid of COVID-19 patients, Cell division control protein 42 (CDC42) and G protein 1137 subunit alpha Q (GNAQ) were both upregulated. CDC42 belongs to GTPase family involved in 1138 the thrombin formulation process 278 and GNAQ also belongs to G proteins and is involved in 1139 thrombin signaling 279 . The upregulated CDC42 and GNAQ may indicate the coagulation response 1140 in the thyroid. Besides, two kinds of coagulation associated protease inhibitors, serine protease 1141 inhibitors (SERPINs) family 280 and alpha-2-macroglobulin (A2M), were all downregulated in the 1142 thyroid of COVID-19 patients ( Figure S7D ), which could suppress plasmin and kallikrein 53 . 1143 Kininogen-1 (KNG1), an alpha-2-thiol protease inhibitor, was also downregulated in the thyroid 1144 of COVID-19 patients ( Figure S7D ), which could disturb kinin-kallikrein system 281 . 1145 Neuroendocrine convertase 2 (PCSK2), insulin receptor (INSR) and carboxypeptidase E 1146 (CPE) all participate the insulin processing and their secretion is regulated by mTOR in insulin 1147 resistance 282 , which also matched with our data ( Figure S7D ). 1148 Altogether, the thyroid is mainly affected by the inflammatory response after virus infection, 1149 in which the activated NF-κB and mTOR signaling could have an association with coagulation, 1150 insulin resistance and VEGF involved angiogenesis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint sterol reductase TM7SF2 (TM7SF2). 1165 Although those proteins are unrelated to the virus directly, the cholesterol synthesis is 1166 associated with steroid hormones such as testosterone. The low intracellular concentration of 1167 sterols would induce the cleavage of membrane bound sterol response element-binding protein 1168 (SREBP) by SREBP cleavage-activation protein (SCAP), then cleaved SREBP in the cytosol 1169 would enter the nucleus to activate expression of proteins participated in cholesterol biosynthesis 1170 and uptake process 283 . 1171 Delta (14)-sterol reductase is encoded by TM7SF2, which can be activated in response to low 1172 cell sterol levels mediated by SREBP2 284 . TM7SF2 is detected in Leydig cells specifically by 1173 antibody staining 285 , the decrease of which suggested impaired Leydig cell population or function. 1174 We also found a Leydig cell biomarker, INSL3, was decreased (SI Figure 15 ). might associates with diabetes 296 as well. 1186 The hypothalamic-pituitary-gonadal (HPG) axis comprises of pulsatile GnRH from the 1187 hypothalamus. It will impact on the anterior pituitary to induce expression and release of both LH 1188 and FSH into the circulation. These will, in turn, stimulate receptors on testicular Leydig and 1189 Sertoli cells, respectively, to promote steroidogenesis and spermatogenesis. Both Leydig and 1190 Sertoli cells exhibit negative feedback to the pituitary and/or hypothalamus via their products 1191 testosterone and inhibin B, respectively, thereby allowing tight regulation of the HPG axis. In 1192 particular, LH exerts both acute control on Leydig cells by influencing steroidogenic enzyme 1193 activity, as well as chronic control by impacting on Leydig cell differentiation and gene 1194 expression 287 . 1195 Significantly decreased INSL3 indicates the decreased number of mature Leydig cells in the 1196 patients with COVID-19, which is consistent with the HE staining images ( Figure 7B , C). 1197 Interestingly, Ma et al observed significantly elevated serum luteinizing hormone (LH) and 1198 dramatically decrease in the ratio of testosterone (T) to LH and the ratio of follicle stimulating 1199 hormone (FSH) to LH, while no statistical difference in serum T (p=0.0945) or FSH 1200 (p=0.5783) 297 . We inferred the change on LH might be caused by the reduced number of mature 1201 Leydig cells, which would cause the decreased serum T. Weakened negative feedback from 1202 Leydig cells might promote the secretion of LH. 1203 FASN, ACLY, SQLE and FDFT1 all participate in lipid synthesis directly. Fatty acid synthase 1204 is a key enzyme in de novo lipogenesis. FASN is markedly inactivated under conditions of insulin 1205 resistance and is a potential biomarker for insulin resistance 298 . Reduced FASN suggested the 1206 progression of insulin resistance in COVID-19 patients. This protein has been discussed in the 1207 fibrosis process associated proteins. 1208 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint ACLY is the enzyme primarily responsible for the production of extramitochondrial acetyl-1209 CoA and is thus strategically positioned at the intersection of glycolytic and lipidic metabolism 299 , 1210 which make it a potential target for lipid lowing 300 . FDFT1 and SQLE play an important role in 1211 the cholesterol biosynthesis pathway, and both of them are effective targets in the treatment of 1212 hypercholesterolemia 301,302 . ACLY, SQLE and FDFT1 were observed downregulated in the testis 1213 tissue of COVID-19 patients compared with non-COVID-19 controls (SI Figure 15) , which was 1214 consistent with a previous study discovering lower levels of low-density lipoprotein cholesterol 1215 and total cholesterol levels in COVID-19 patients as compared with normal subjects 303 . 1216 There are two dysregulated proteins associated with sperm generation. RNF216 is essential 1217 for spermatogenesis and male fertility 304 . The deletion of Drc7 leads to aberrant tail formation in 1218 mouse spermatozoa that phenocopies patients with multiple morphological abnormalities of the 1219 sperm flagella (MMAF) 305 . These two proteins were reduced in COVID-19 patients (SI Figure 1220 15), suggesting the impairment of spermatogenesis and sperm motility caused by SARS-CoV-2 1221 infection. 1222 Store-operated calcium entry-associated regulatory factor (SARAF) was downregulated in 1223 the testis of COVID-19 patients (SI Figure 15 ), which inactivates the store operated calcium entry 1224 machinery to prevent excess calcium refilling 306 . 1225 In is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted August 19, 2020. . https://doi.org/10.1101/2020.08.16.20176065 doi: medRxiv preprint The y-axis stands for the protein expression ratio by TMT-based quantitative proteomics. Pair-1233 wise comparison of each protein between COVID-19 patients and control groups was performed 1234 with student's t test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. 1235 1236 expression and lipid homeostasis. Cell Biol SI Figure 12| Characteristic proteins in the heart of COVID-19 patients (a), (b) The 1048 stimulated inflammatory mediators and dysregulated endothelial cells would cause vascular 1049 hyperpermeability. (c) Hypoxia related protein alteration. (d) ATP generation in mitochondria Upregulation pathway (or biological process) is 1052 present by red box with white font and downregulation pathway (or biological process) is green 1053 box with white font. Blue box represents the pathology of heart Diffuse proximal tubule injury, brush border lost and microthrombus were observed in 1058 the pathological sections of the cortex, while occasional cellular swelling and atrophy were also 1059 observed in the medulla (Fiugre S1). Generally, more damage was observed in pathological 1060 sections in the renal cortex than in the renal medulla By IPA analysis, 1066 the LPS/IL-1 mediated inhibition of RXR function, acute phase response, IL-8 signaling, 1067 necroptosis and neuroinflammation signaling pathways were found to be upregulated in both 1068 cortex and medulla (SI Figure 13a). Meanwhile, the activated status of the enriched pathways in 1069 the renal cortex are more drastic than in the renal medulla (SI Figure 13a). Besides, the 1070 upregulated pathways including signaling by Rho Family GTPase, Toll−like receptor signaling, 1071 IL-6 signaling and NF -κB signaling and the downregulation pathways including fatty acid 1072 beta−oxidation I, glycolysis and gluconeogenesis were also specifically enriched in the renal 1073 cortex. Thus, at both pathological and molecular levels COVID-19 patients, lipopolysaccharide-binding protein (LBP), interleukin-1 receptor 1 LBP could bind to the pathogen 1077 lipopolysaccharides (LPS) and enhance CD14 and Toll-like receptors, which may be the cause of 1078 pathogenic infection and sepsis in these COVID-19 patients 258 The IL1R1 was found to be upregulated in 1080 COVID-19 patients, as well as sepsis 259,260 . Upregulation of the downstream NF-κB complexes 1081 and CCAAT enhancer binding protein beta (CEBPB) were also observed, leading to activation of 1082 IL-6, IL-8, iNOS and TNFR1 signaling pathways 261 . Besides, activated signal transducer and 1083 activator of transcription 1 (STAT1) and receptor interacting serine/threonine kinase In addition to inflammatory and infection-related proteins, we also detected the upregulation 1086 of hypoxia inducible factor 1 subunit alpha (HIF1A) in the cortex, which could promote TRL2, 1087 vWF overexpression and nitric oxide (NO) generation HIF1A could suppress energy metabolism-related pathways including fatty acid β-1089 oxidation and gluconeogenesis to exacerbate insulin resistance 266 . As the main ATP provider in the 1090 renal proximal tubular cells, the inhibition of fatty acid β-oxidation would block energy supply 1091 and lead to aggravate kidney injury 266 . Interestingly, among seven organs, kidney is the only one 1092 in which ACE2 was downregulated The downregulation of ACE2 could mediate Ang II accumulation and induce the 1095 upregulation of vascular cell adhesion molecule 1 (VCAM1) 267 , a marker for sepsis and kidney 1096 injury 268,269 . Likewise, Ang II regulates RhoGTPase via G Protein-Coupled Receptor (GPCR), 1097 indeed the Gα, Gβ and RhoGTPase including RHO and CDC42 were all upregulated in COVID-1098 19 patients. ROCK1, a downstream molecular of RHO, was upregulated as well, which could lead 1099 to renal tubular injury, inflammation and fibrogenesis 270,271 . CDC42 induced CDC42EP4 is an 1100 upstream regulator of SEPTIN family and the upregulated SEPTIN6, SEPTIN7, SEPTIN8 and 1101 SEPTIN9 could induce fibrogenesis in kidney as well, which means SARS-CoV2 infection may 1102 cause chronic injury and SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is 1238 Blocked by a Clinically Proven Protease Inhibitor CD209L (L-SIGN) is a receptor for severe acute respiratory 1241 syndrome coronavirus Homozygous L-SIGN (CLEC4M) plays a protective role in SARS 1244 coronavirus infection COVID-19 and the cardiovascular 1246 system The Science Underlying COVID-19: Implications 1248 for the Cardiovascular System Renin-Angiotensin-Aldosterone System Inhibitors in 1251 Patients with Covid-19 A novel angiotensin-converting enzyme-related 1254 carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 A dendritic cell-specific intercellular adhesion molecule 3-1257 grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver 1258 sinusoidal endothelial cells and promotes HIV-1 infection The C-type lectin receptor CLEC4M binds, internalizes, and clears 1261 von Willebrand factor and contributes to the variation in plasma von Willebrand factor 1262 levels L-SIGN (CD209L) and DC-SIGN (CD209) mediate 1264 transinfection of liver cells by hepatitis C virus Cathepsin L-selective inhibitors: A 1267 potentially promising treatment for COVID-19 patients Human Coronavirus: Host-Pathogen Interaction Small molecule inhibitors reveal Niemann-Pick C1 is essential 1272 for Ebola virus infection The Role of Lipid Metabolism in COVID-19 Virus Infection 1274 and as a Drug Target The N-terminal domain of 1276 the murine coronavirus spike glycoprotein determines the CEACAM1 receptor specificity 1277 of the virus strain CEACAM1 regulates TIM-3-mediated tolerance and 1279 exhaustion CEACAM1 regulates insulin clearance in liver The nuclear factor NF-kappaB pathway in inflammation Nuclear factor-kappaB: activation and regulation 1285 during toll-like receptor signaling Germline mutations in NFKB2 implicate the noncanonical NF-1287 kappaB pathway in the pathogenesis of common variable immunodeficiency Aberrant rel/nfkb genes and activity in human cancer CCAAT enhancer-binding protein beta is required for 1292 normal hepatocyte proliferation in mice after partial hepatectomy Targeted disruption of the NF-IL6 gene discloses its essential 1295 role in bacteria killing and tumor cytotoxicity by macrophages Regulation of STAT-dependent 1298 pathways by growth factors and cytokines The role of STATs in apoptosis Thrombin regulates 1302 vascular smooth muscle cell growth and heat shock proteins via the JAK-STAT pathway STATs in cancer inflammation and immunity: a 1305 leading role for STAT3 AP-1 subunits: quarrel and harmony 1307 among siblings AP-1 as a regulator of cell life and death RB1: a prototype tumor suppressor and an enigma The retinoblastoma protein induces apoptosis directly at 1313 the mitochondria Proteomic analysis of cap-dependent translation identifies 1315 LARP1 as a key regulator of 5'TOP mRNA translation A SARS-CoV-2 protein interaction map reveals targets for 1318 drug repurposing Hypoxia signaling in human diseases 1320 and therapeutic targets Hepatocyte nuclear factor 4-alpha involvement in 1322 liver and intestinal inflammatory networks Overview of the coagulation system Inflammation and thrombosis: roles of neutrophils, platelets 1327 and endothelial cells and their interactions in thrombus formation during sepsis Distinct contributions of complement factors to platelet 1330 activation and fibrin formation in venous thrombus development Tissue factor pathway inhibitor and the revised theory of 1333 coagulation Contact system: a vascular biology modulator 1335 with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes Factor XIII: a 1338 coagulation factor with multiple plasmatic and cellular functions Role of von Willebrand factor in the 1341 haemostasis The Coagulation Factors Fibrinogen, Thrombin, and Factor XII 1343 in Inflammatory Disorders-A Systematic Review Protein C anticoagulant and 1346 cytoprotective pathways Physiologic inhibition of human activated protein C 1349 by alpha 1-antitrypsin Protein C 1351 inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of 1352 protein C in human plasma Septic shock, multiple organ failure, and disseminated 1354 intravascular coagulation. 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One is 1007 vasogenic edema with mild infiltration of inflammatory cells, and the other is myocardial cell 1008 edema ( Figure S1 ). 1009Vasogenic edema is mainly caused by the change of vascular permeability, which induces the 1010 serum fluids to flow into interstitium. The increase of vascular permeability is usually caused by 1011inflammation 246, 247 . Several inflammatory mediators were elevated in the heart tissue of COVID-1012 19 patients, including matrix metalloproteinases 9 (MMP9), C5a anaphylatoxin chemotactic 1013 receptor 1(C5AR1), interferon gamma receptor 1 (IFNGR1) and several other cytokines (Fiugre 1014 S7A, SI Figure 12a ). Importantly, histamine N-methyltransferase (HNMT), which catabolizes 1015 histamine, was significantly downregulated and may lead to histamine accumulation and vascular 1016 hyperpermeability 247 . The accumulation of inflammatory mediators, such as C5a and histamine, 1017 could induce the P-selectin expression and result in leukocyte extravasation 248 (SI Figure 12b ). 1018The above findings were also supported by the upregulation of intercellular adhesion molecule 1 1019(ICAM-1), which involves in leukocyte adhesion and trans-endothelial migration 249 and MMP9, 1020which facilitates matrix degradation and is believed to contributes to inflammatory cell 1021 invasion 250 . Physiologically consistent, we observed inflammatory cell infiltration by 1022hematoxylin-eosin staining sections ( Figure S1 ). 1023Myocardial cell edema is caused by the movement of osmotically active molecules from the 1024 extracellular to the intracellular space including sodium, chloride and water. One of the underlying 1025 pathological mechanisms was the reduced ATP availability in the mitochondria due to dysfunction 1026 of sodium (Na + ), potassium (K + ) ATPase 251 under hypoxia, inflammation and other conditions 252 . 1027These observations strongly indicated a hypoxia situation in COVID-19 patients, and we also 1028 observed consistent molecular changes under hypoxia (SI Figure 12 c