key: cord-0980355-nwlg8avm authors: Zhang, Shilei; Wang, Lulan; Cheng, Genhong title: The Battle between Host and SARS-CoV-2: Innate Immunity and Viral Evasion Strategies date: 2022-02-14 journal: Mol Ther DOI: 10.1016/j.ymthe.2022.02.014 sha: 8c01cf9af210c74e62d93da1b88077dce56e463e doc_id: 980355 cord_uid: nwlg8avm The SARS-CoV-2 virus, the pathogen causing COVID-19, has caused more than 200 million confirmed cases, resulting in more than 4.5 million deaths worldwide by the end of August, 2021. Upon detection of SARS-CoV-2 infection by pattern recognition receptors (PRRs), multiple signaling cascades are activated, which ultimately leads to innate immune response such as induction of type I and III interferons, as well as other antiviral genes that together restrict viral spread by suppressing different steps of the viral life cycle. Our understanding of the contribution of the innate immune system in recognizing and subsequently initiating a host response to an invasion of SARS-CoV-2 has been rapidly expanding from 2020. Simultaneously, SARS-CoV-2 has evolved multiple immune evasion strategies to escape from host immune surveillance for successful replication. In this review, we will address the current knowledge of innate immunity in the context of SARS-CoV-2 infection and highlight recent advances in the understanding of the mechanisms by which SARS-CoV-2 evade host’s innate defense system. Coronaviruses are enveloped positive-sense single-stranded RNA viruses in the 26 Coronaviridae family, which have a broad spectrum of hosts such as humans, bats, camels， 27 and avian species, including livestock and companion animals, posing a threat to public 28 health. 1 Coronaviruses are classified in the subfamily of Orthocoronavirinae, which is 29 further divided into four genera, based on differences in protein sequences: α-coronavirus, 30 β-coronavirus, γ-coronavirus, and δ-coronavirus. 2 The α-coronaviruses and β-31 coronaviruses only infect mammals, whereas γ-coronaviruses and δ-coronaviruses 32 primarily infect birds, though some of them can infect mammals. 3 TLR4 is a remarkable PRR that recognizes multiple PAMPs from bacteria, viruses, and 168 other pathogens. 52 In addition, TLR4 also senses certain damage-associated molecular 169 patterns (DAMPs) such as high mobility group box 1 (HMGB1) 53 and heat shock proteins 170 (HSPs) 54 released from dying or lytic cells during host tissue injury or viral infection. Like 171 TLR2, TLR4 has also been reported to sense several viral proteins after infection, including 172 the fusion protein of respiratory syncytial virus (RSV) 55 , the glycoprotein of EBOV 56 , the 173 glycoprotein of vesicular stomatitis virus (VSV G) 57 , and the dengue virus (DENV) 174 nonstructural protein 1 (NS1). 58 Sohn et al. recently reported that the expression of TLR4 175 itself and its downstream signaling mediators including TRAF6, IRAK1, and TRIF in 176 COVID-19 patients were significantly upregulated in peripheral blood mononuclear cells, 177 compared to those in healthy controls, which indicated a correlation between increased 178 TLR4 expression and its activation by a component of the SARS-CoV-2 virus, similar to 179 that which occurs in bacterial sepsis. 59 50 These 217 preliminary findings reveal essential roles for TLR7-and IRF7-dependent signaling in the 218 control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit 219 in selected patients, at least early in the course of SARS-CoV-2 infection. 220 RLRs encompass three members, RIG-I, melanoma differentiation-associated protein 5 222 The immune imbalances in COVID-19 are characterized by poor type I IFNs production 319 and an exacerbated release of proinflammatory cytokines, contributing to the severe 320 manifestations of the disease. 103 Several studies have uncovered the multitude of strategies 321 employed by SARS-CoV-2 to limit the global cellular antiviral state, both directly and 322 indirectly (Table 1) . This is assumed to be mostly due to viral targeting of the IFN-323 induction and signaling cascades at multiple levels, as described below (Figure 4) . The traditional design and screen of antivirus drugs often target viral proteins which offer 516 a substantial benefit, as identified compounds may be more specific against viruses and 517 have fewer side effects on humans. However, as an RNA virus, SARS-CoV-2 has high a 518 high rate of mutation leading to the constant generation of many different strains with an 519 altered viral evasion or resistant protein which could render the therapy ineffective. 164, 165 520 Thus, developing novel antivirals targeting virus-host innate immune interaction offers a 521 huge potential for alleviating the pathology of virus infections as well as assisting the 522 immune system to clear viral infection. The strategies for design antiviral drugs based on 523 the knowledge of crosstalk between virus and host innate immune can be divided into 524 several categories: (1) targeting TLRs and CLRs as well as NF-κB to prevent 525 hyperinflammation in COVID-19; (2) designing novel IFN agonists with comparable or 526 better antiviral activities but with less toxicity than IFN itself; (3) targeting ISGs that 527 produce natural antiviral products, like CH25 produces natural antiviral 25HC; (4) 528 screening compounds that can target both viral protein and host innate immune. The 529 increasing knowledge on the interaction between viruses and hosts has been and continues 530 to guide the development of broad-spectrum antiviral drugs not only fight against SARS-531 CoV-2 but also regulate the host immune system. The conception and design of the paper were done by S.Z. and G.C., The initial draft was 564 completed by S.Z., and L.W. Editing and further drafts were done by S.Z. and G.C. All 565 authors reviewed the final version of the paper. 566 567 The authors declare no conflict of interest. 569 Variant analysis of 1 SARS-CoV-2 600 (COVID-19) by the numbers. 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Front 1080 Microbiol 12 Recognition Receptors; TLR: Toll like receptors; CLR: C-type lectin receptors ; ISG: 1103 Interferon-stimulated gene Figure 3. PRRs-mediated recognition of SARS-CoV-2 SARS-CoV-2 is recognized by the innate immune system by members of distinct classes 1106 of PRRs (with their respective ligands indicated): Toll like receptors (TLRs), retinoic acid Upon recognition, 1108 signal transduction occurs through downstream transcription regulators called interferon 1109 regulatory factors (IRFs) to elicit interferons production. The secreted interferons interact 1110 with their receptors, which results in activation of JAK-Stat signaling pathway that governs 1111 the expression of various IFN-stimulated genes TRAF6: TNF receptor associated factor 6; MAPK: Mitogen-activated protein kinase Activator protein 1; IKKs: IκB kinase; NF-κB: Nuclear factor kappa-light-chain-enhancer 1114 of activated B cells; TRIF: TIR domain-containing adaptor-inducing interferon-β; TRAF3: 1115 TNF receptor associated factor 3; IKKe: IkappaB kinase-epsilon kinase 1; IRF3: Interferon regulatory factor 3; Syk: Spleen tyrosine kinase; Card9: Caspase 1117 recruitment domain family member 9 Mucosa-associated lymphoid tissue lymphoma translocation protein 1; IFNAR: Interferon 1119 Tyrosine-protein kinase JAK1; Tyk2: Non-receptor tyrosine-1120 protein kinase 2; IFNLR1: Interferon Lambda Receptor 1; IL10Rβ: Interleukin 10 receptor 1121 subunit beta; Stat1: Signal transducer and activator of transcription 1; Stat2: Signal 1122 transducer and activator of transcription 2; IRF9: Interferon regulatory factor 9 Interferon-stimulated gene factor 3; GAS: Gamma interferon activation site; ISRE: 1124 Interferon-sensitive response element Figure 4. Innate immune evasion by SARS-CoV-2 Recognition by PRRs triggers a signaling cascade that culminates in the transcription and 1127 subsequent generation of interferons. SARS-CoV-2 has evolved to antagonize these 1128 pathways at virtually stages, indicated by red blunt end arrows. Read solid arrows indicate 1129 hyper activated signal cascade by SARS-CoV-2. Black solid arrows indicated pathway 1130 connection