key: cord-1010181-k5596dab
authors: Wen, Zeyu; Zhang, Yue; Lin, Zhekai; Shi, Kun; Jiu, Yaming
title: Cytoskeleton—a crucial key in host cell for coronavirus infection
date: 2020-07-27
journal: J Mol Cell Biol
DOI: 10.1093/jmcb/mjaa042
sha: 4cae75ed8a73a9abc5978da655b0ba6d5d1b23a5
doc_id: 1010181
cord_uid: k5596dab

The emerging coronavirus pandemic is threatening the public health all over the world. Cytoskeleton is an intricate network involved in controlling cell shape, cargo transport, signal transduction, and cell division. Infection biology studies have illuminated essential roles for cytoskeleton in mediating the outcome of host‒virus interactions. In this review, we discuss the dynamic interactions between actin filaments, microtubules, intermediate filaments, and coronaviruses. In one round of viral life cycle, coronaviruses surf along filopodia on the host membrane to the entry sites, utilize specific intermediate filament protein as co-receptor to enter target cells, hijack microtubules for transportation to replication and assembly sites, and promote actin filaments polymerization to provide forces for egress. During coronavirus infection, disruption of host cytoskeleton homeostasis and modification state is tightly connected to pathological processes, such as defective cytokinesis, demyelinating, cilia loss, and neuron necrosis. There are increasing mechanistic studies on cytoskeleton upon coronavirus infection, such as viral protein‒cytoskeleton interaction, changes in the expression and post-translation modification, related signaling pathways, and incorporation with other host factors. Collectively, these insights provide new concepts for fundamental virology and the control of coronavirus infection.

2020. In addition to affecting human health, some of the CoVs also seriously threaten the animal husbandry, as summarized in Table 1 . In this review, we only focus on the CoVs that have been reported to interact with host cytoskeletons.

Cytoskeleton is an intricate network in eukaryotic cells, which comprises three major types of cytoskeletal polymers including actin filaments (AFs), microtubules (MTs), and intermediate filaments (IFs) , allowing cells to perform multiple functions in a united way, such as connecting to the external environment, coordinating forces to move and change shapes, transporting vesicles through the cytoplasm, and spatially organizing the contents (Fletcher et al., 2010; Wickstead et al., 2011) .

AFs are most abundant polymers for large number of cells. Actin exists in monomeric form as globular actin or G-actin, and in filamentous form called F-actin or microfilaments (Dohner et al., 2005) . Quick assembly and disassembly are regulated by a variety of actin-binding proteins, which enable AFs to provide mechanical support, determining cell shape, migration, and division (Pollard et al., 2003) . Importantly, AFs can construct sheet-like extensions such as lamellipodia, membrane ruffles, and blebs, finger-like protrusions like microvilli and filopodia, or dot-like podosomes (Taylor et al., 2011) . The actin cortex beneath the plasma membrane can be a barrier for virus entry or egress (Marsh et al., 1997) . Moreover, with the help of motor protein myosin, AFs can serve as tracks for short-range transport of cargoes.

MTs are long, hollow cylindrical polar structures with a dynamic plus-end and minus-end, assembled by heterodimers of α-and β-tubulin (Desai et al., 1997; Downing, 2000; Dohner et al., 2005) . The minus-ends of MTs are often attached to the sites where MTs are nucleated, and the most essential activity is to form different types of microtubule-organizing centers (MTOCs), whereas plus-ends are pointing to plasma membrane, which contributes to the intracellular transportation of MT-bound vesicles (Wu et al., 2017; Akhmanova and Steinmetz 2019) . The coexistence of assembly and disassembly at the ends generates dynamic and unstable characteristics of MTs. Importantly, MTs combine with motor protein families to take part in long-distance transport in neuronal dendrites and axons (Prokop, 2013) . MTs are also key components of respiratory cilia. Thus, the homeostasis of MTs is closely related to neurological and respiratory diseases.

Among these filaments, IFs are distinguished by the medium size (~10 nm-diameter) compared to AFs (~7 nm) and MTs (~24 nm) (Franke et al., 1978) . Over 70 proteins encode IFs and their expressions vary with cells and tissues. Based on the structure and sequence composition, IFs proteins are classified into six types, including keratins (types I and II); desmin, glial fibrillary acidic protein (GFAP), and vimentin (type III); neurofilaments, nestin, and α-internexin (type IV); nuclear lamins (type V); and filensin and phakinin (type Ⅵ or others) (Herrmann et al., 2007; Lowery et al., 2015; Yoon and Leube 2019) . Unlike AFs and MTs, IFs are more stable, usually surround the nucleus, and extend throughout the cytoplasm, serving as scaffolds and participating in intracellular organization, membrane trafficking, and signaling transduction (Lowery et al., 2015) . More and more studies demonstrate that abnormalities of IFs lead to severe pathogenesis like epithelial to mesenchymal transition (EMT) and neuronal diseases (Liem et al., 2009; Rout-Pitt et al., 2018) .

Over the years, extensive studies have discovered that most viruses hijack cytoskeleton network to fulfill their own infection (Foo et al., 2015; Denes et al., 2018; Miranda-Saksena et al., 2018; Bedi et al., 2019; Zhang et al., 2019) , which inspires a wide variety of exciting research avenues. In this review, we outline the important roles of AFs, MTs, and IFs in the life cycle of CoVs and analyze the relationship between host cytoskeleton and CoVs-induced pathological changes.

After binding to the target cell, viruses must migrate to favorable sites for entry, usually by virus surfing (Figure 2A) . A study using porcine hemagglutinating encephalomyelitis virus (PHEV) labeled with the lipophilic fluorescent dye DiD revealed that bound viruses surfed toward the foot of filopodia via actin retrograde flow at ~30 min post infection. During this process, AFs depolymerized and transient blebs were formed on the cell surface (Li et al., 2017) . Similar results were also observed in porcine epidemic diarrhea virus (PEDV)-and transmissible gastroenteritis coronavirus (TGEV)-infected IPEC-J2 cells. After viruses reached the entry site, AFs retracted and concentrated around plasma membrane. Then actin bundles lined with plasma membrane for virus internalization (Zhao et al., 2014) . Pharmacological stabilization of actin cortex by jasplakinolide prevented HCoV-OC43, HCoV-NL63, and PHEV from penetrating host cells and resulted in retention of virions on actin cortex or unstructured actin deposits, suggesting that CoV internalization requires dynamic actin rearrangements (Li et al., 2017; Milewska et al., 2018; Owczarek et al., 2018) .

Besides, viruses also take advantage of cytoskeleton-regulating signaling pathways as part of their infection processes (Figure 3 ).

Previous studies have shown that TGEV and PHEV could induce cofilin phosphorylation by activating cellular EGFR-PI3K-Rac1/Cdc42-PAK-LIMK signaling pathway at the early stage of infection, thereby causing F-actin polymerization and rearrangement and further promoting virus entry ( Figure 3A ) (Hu et al., 2016; Lv et al., 2019) . Blocking Rac1 and Cdc42 signal transduction by ethylisopropyl amiloride inhibits murine coronavirus (MHV) infection ( Figure 3B ) (Koivusalo et al., 2010) . These results suggest that dynamic actin cytoskeleton and relevant signaling pathways strongly contribute to virus entry.

Nevertheless, membrane-actin linker ezrin could interact with SARS-CoV S endodomain and hinder virus entry and fusion ( Figure 2A ). Knock-down of ezrin or expression of dominant-negative (DN) ezrin increases virus entry (Millet et al., 2012 (Millet et al., , 2015 . Further analysis identified that the F1 lobe of ezrin FERM domain, the last 8 C-terminal residues, and the membrane proximal cysteine cluster of SARS-CoV S endodomain are responsible for this interaction (Millet et al., 2012) . Another study found that N protein of porcine deltacoronavirus (PDCoV) upregulated ezrin, which may further facilitate viral infection by manipulating the host cytoskeleton network and cell signaling (Lee et al., 2015) . These results suggest that AFs cooperate with other host proteins to play dual roles during the entry of CoVs.

After entry, AFs further undergo rearrangement during CoV replication and assembly. In PEDV-or TGEV-infected IPEC-J2 cells, AFs retract from plasma membrane, form a juxtanuclear rings, and bind to virus particles near nuclear membrane ( Figure 2C ), supporting viral genome replication and viral protein synthesis. Disruption of AF dynamics by jasplakinolide or cytochalasin D blocked actin ring formation and inhibited replication and release of PEDV, TGEV, and infectious bronchitis virus (IBV) (Surjit et al., 2004; Gov et al., 2006; Wang et al., 2009; Zhao et al., 2014; Sun et al., 2017) . AF reorganization can be induced by viral protein expression and related signaling pathway. SARS-CoV N protein induces p38 mitogen-activated protein kinase (MAPK) cascade, which plays an important role in actin remodeling ( Figure 3C ) (Surjit et al., 2004; Gerits et al., 2007; Zhao et al., 2014) .

Moreover, actin-binding protein filamin A interacts with TGEV S protein, which is essential for the retention of S protein at the ERGIC (Trincone et al., 2015) .

The budding and egress of CoVs are mainly related to AFs. Previous study found that the interaction between β-actin and M protein of IBV is essential for virus assembly and budding. Further analysis identified that amino acids A159 and K160 on M protein are important for this interaction ( Figure 2C ) (Gov et al., 2006; Wang et al., 2009 ). Moreover, a study using atomic force microscope and scanning electron microscopy has shown that SARS-CoV infection resulted in proliferation of pseudopodia and thickening of AFs below the subcellular surface at the late stage of infection, which may provide the bending force to extrude the virus particles ( Figure 2D ) (Ng et al., 2004) . Together, these results indicate that actin network involves in assembly and expelling of the progeny CoV particles probably by providing additional force for membrane bending. Roles of AFs and related proteins at different stages of CoVs life cycle are summarized in Table 2 .

Dynamin, a microtubule-related protein, is responsible for the endocytic process of feline infectious peritonitis virus (FIPV), MHV, and HCoV-NL63 infections (Figure 2A ), and dynamin inhibitory peptide, siRNA of dynamin, and DN dynamin all effectively block virus internalization Burkard et al. 2014; Milewska et al., 2018) . However, the internalization of viral protein-antibody complexes in FIPV-infected monocytes did not require Rho-GTPases, actin, or dynamin, which is contrary to FIPV internalization Van Hamme et al., 2008) . These results indicate the complexity of MTs-associated CoV entering processes.

Once entering host cell, CoVs-containing vesicles run along MTs to move from the plasma membrane toward replication sites ( Figure 2B ). By visualizing the endocytosis process during FIPV infection, it was found that internalized vesicles were associated with MTs just 1 min after initial internalization. After 10 min, CoVs-containing vesicles reached MTOC. Chemical stabilization or depolymerization of MTs cannot block endocytosis but keep the vesicles close to the plasma membrane, instead of being transported to the cell center (Dewerchin et al., 2014) . These results suggest that MTs are critical in guiding the transportation of internalized CoVs-vesicles.

CoVs can be transported from the ER to Golgi apparatus (GA) for assembly, which is in a MT-dependent manner ( Figure 2C ). Double-membrane vesicles (DMVs) that associate with RTCs are considered as the CoV replication site, whereas exppresion of SARS-CoV NSP6 can also induce single-membrane vesicles surrouding MTOC (Hagemeijer et al., 2010; Angelini et al., 2013) .

MT-associated protein 1 light chain 3 (LC3) could act as the cross-node of multiple pathways to take part in the formation process of DMV during the infection of MHV, SARS-CoV, and IBV (Prentice et al., 2004a, b; Cottam et al., 2011; Reggiori et al., 2011; Maier et al., 2013) . Nonstructural protein 2 (NSP2) of MHV is recruited to RTCs by virtue of its C terminus and associated with DMV The viral evolutionary homolog can mimic fundamental cell process for the sake of the viral life cycle. For instance, residues 328-340 of neurotropic murine coronavirus (JHMV) N protein were found to be aligned optimally with MT-binding domain of tau, where overall 20% identity and 42% similarity were uncovered. The amino acid sequence homology between N protein and tau provides a possible molecular mechanism for the interaction between viral protein and MTs (Pasick et al., 1994; Kalicharran et al., 1995) . Roles of MTs at different stages of CoV life cycle are summarized in Table   3 .

The replication cycle of CoVs is initiated by the binding of S protein to cell surface receptors (Fung et al., 2019) . Intriguingly, vimentin IFs could act as the co-receptor to participate in the process of virus entry. For instance, SARS-CoV infection increases the expression of vimentin, and cell surface vimentin cooperates with angiotensin-converting enzyme 2 (ACE2) to construct the receptor for SARS-CoV S protein. Anti-vimentin antibody successfully blocked virus entering Vero E6 cells and its neutralizing efficiency was close to that of anti-ACE2 antibody, indicating that vimentin has the potential to be a target for antiviral therapies (Figure 2A ) (Yu et al., 2016) . In addition, vimentin can bind to N protein of TGEV, and knockdown of vimentin significantly decreased cell-associated virus, suggesting that vimentin plays an essential role in CoV replication (Zhang et al., 2015) . Furthermore, cytokeratin 18 (CK18)-expressing epithelial cells are the prevailing target of MERS-CoV, rather than CK5/6 or CK14-expressing cells, indicating that various types of IFs are related to cell tropism of CoVs (Haverkamp et al., 2018) . Specific events in which IFs participate are listed according to the genera of viruses as well as the phases during infection (Table 4) .

CoVs could utilize comprehensively three cytoskeleton networks to complete viral transport process.

Transport from/to the cell periphery for short-range route is mediated by actin and its motor proteins like myosin, while long-range transport is mediated by MTs and the motor proteins dynein and kinesin (DePina et al., 1999; Langford, 2002; Dewerchin et al., 2014; Robinson et al., 2017) . In FIPV-infected monocytes, small actin tails, myosin light chain kinase (MLCK), and myosin 1 cooperate with MTs to participate in the intracellular trafficking of internalized vesicles, which may be conducive to switch tracks from AFs to MTs ( Figure 2B ) (Dewerchin et al., 2014) . The propagation of swine hemagglutinating encephalomyelitis virus depends on MTs and IFs in neurons, which facilitate virus to be transported along the neuron cell body and axonal terminals (Hara et al., 2009 ). Moreover, dynamin 2 assists with actin to participate in the internalization of TGEV witnessed by single-virus tracking (Wang et al., 2020) .

Cytoskeleton components were found to be candidates emerged from several CoV infection-related screens. Two-dimensional difference gel electrophoresis (2D DIGE) coupled with LC-MS/MS identified 33 differentially expressed proteins in TGEV-infected swine testes cells.

Surprisingly, 35.3% of them are cytoskeleton-related proteins such as β-actin, α-tubulin, keratin 19, http://mc.manuscriptcentral.com/jmcb and vimentin (Zhang et al., 2013) . Another study identified numerous cytoskeletal and related proteins that associate with IBV virion, including tubulin α1 chain, tubulin β3 chain, tubulin β4 chain, tubulin β7 chain, vimentin, myosin-9, annexin A2, and actin α cardiac muscle 1 (Dent et al., 2015) .

Moreover, IBV infection upregulates the expression of vimentin and actin (Emmott et al., 2010) . The proteomic analysis also found that the abundance of α-tropomyosin and vimentin increases with the virulence of IBV strains (Cao et al., 2012) . Together, multi-cytoskeleton components involved in CoV infection are listed in Table 4 , and these results indicate that cytoskeleton networks are tightly associated to CoV infection.

CoV infection can change the normal cytokinesis by affecting AFs. Elongation factor 1-α (EF1α) interacts with F-actin and promotes F-actin bundling, which is essential for the formation of contractile ring during cytokinesis (Yang et al., 1990; Kurasawa et al., 1996; Numata et al., 2000; Gross et al., 2005) . Using yeast two-hybrid screen, it has been identified that the C terminus (amino acids 251-422) of SARS-CoV N protein interacts with EF1α and induces aggregation of EF1α, which destroys the bundling of F-actin, thereby inhibiting protein translation and cytokinesis ( Figure   2C ) (Zhou et al., 2008) .

AFs and MTs participate in the formation of syncytia induced by CoV infection. For example, MHV and SARS-CoV infections induce macropinocytosis, accompanied by membrane ruffling and extensive filopodia, which can facilitate S protein-receptor interactions with neighboring cells and thereby is important for virus replication and cell-cell fusion (Freeman et al., 2014) (Figure 2C ). In addition, MTs participate in the translocation of fragmented GA during CoV infection. Previous study has shown that GA was fragmented and translocated to the center of the syncytia, while MTs were rearranged and radiated towards syncytia in MHV infection, suggesting that MTs perhaps provide guidance for the transportation of GA into the center of the syncytia ( Figure 2B ) (Kalicharran et al., 1996; Lavi et al., 1996) .

Several studies have shown that disruption of MTs is related to neurodegenerative diseases. For instance, MHV infection induces tau phosphorylation via glycogen synthase kinase-3β-dependent mechanism, which disrupts MT stabilizing capacity and thereby causes brain damage ( Figure 3B ) (Kalicharran et al., 1995; Sy et al., 2011; Barbier et al., 2019) . The progression of demyelinating disease is correlated with MT-dependent transport. Gap junctions (GJs) formed by connexin 43 (Cx43) and Cx47 are important for maintenance of central nervous system (CNS) homeostasis.

MHV-A59 infection restricted MT-mediated Cx43 delivery to cell membrane via the interaction between MHV N protein and tubulins. Besides, MHV-A59 infection downregulated Cx47 expression, which resulted in GJ loss and further caused demyelination ( Figure 2B ) (Basu et al., 2017) .

Interestingly, chemical disruption of MTs with colchicine and vinblastine significantly inhibits S protein-mediated neuronal transport and subsequent spread of RSA59 (MHV demyelinating strain) whereas RSMHV2 (MHV nondemyelinating strain) remains unaffected. This indicates that RSA59 uses MTs as a conduit for trans-neuronal spread. The difference between these two MHV strains in causing demyelination and axonal loss is determined by the dependence on MTs (Das Sarma et al., 2008 Sarma et al., , 2009 Biswas et al., 2014) .

Structural damage to the respiratory epithelium and abnormal ciliary function are the typical pathologic symptoms of CoV infection. Cilia is a composite structure based on MTs and presents on the cell surface (Soares et al., 2019) . Several studies have found that CoVs with severe respiratory damage such as SARS-CoV, MERS-CoV, IBV, and canine respiratory coronavirus (CRCoV) cause cilia loss in the upper respiratory tract and lung, whereas low toxic HCoV-OC43 does not affect cilia functions (Chilvers et al., 2001; Nicholls et al., 2003; Villarreal et al., 2007; Priestnall et al., 2009; Mitchell et al., 2013; Essaidi-Laziosi et al., 2018; Haverkamp et al., 2018) . These results suggest that the structure of MTs is associated with different pathogenesis of respiratory CoVs, which associates with cilia formation.

Troponin is a regulator of muscle tissue contraction, attached to the tropomyosin on AFs (Lehman et al., 2009) . The level of troponin in the heart muscle of patients was increased during MERS-CoV and SARS-CoV-2 infections (Alhogbani, 2016; Chen et al., 2020; Guo et al., 2020; Inciardi et al., http://mc.manuscriptcentral.com/jmcb 2020; Lippi et al., 2020; Madjid et al., 2020; Shi et al., 2020) . Importantly, patients with severe myocardial damage accompanied by high troponin levels have the higher risk of death (He et al., 2020) .

IFs are also involved in certain cytopathic processes during CoV infection. SARS-CoV papain-like protease induces vimentin IF upregulation and activation of profibrotic cytokines TGF-β1, which results in EMT pathogenesis and fibrosis ( Figure 3C ) (Li et al., 2012) . Moreover, FIPV infection induces high expression of vimentin and mild expression of GFAP in astrocytes with severe inflammatory and necrotic changes, despite that vimentin is normally absent in CNS areas (Poli et al., 1997; Mesquita et al., 2016; Ziolkowska et al., 2017) . These results indicate that vimentin expression could reflect a reactive or degenerative change of astrocytes. Furthermore, modifications in the phosphorylation state of neurofilaments is associated with multiple sclerosis during HCoV-OC43 infection (Tsunoda et al., 2002; Brison et al., 2014) . CoV-related pathological events involved in the host cytoskeleton are listed in Table 5 .

Here, we summarize and highlight that three cytoskeletons AFs, MTs, and IFs are heavily involved in the life cycle and pathological damages caused by CoVs. Regulations between specific viral proteins and cytoskeleton-related proteins were focused and summarized in Table 6 . As we are gaining a greater understanding on the regulation of cytoskeleton components and corresponding elaborate subcellular structures in the process of CoV infections, there are numbers of exciting and substantial questions worth future pursuing.

(i) Since CoVs need to overcome barriers formed by AFs to successfully enter into or egress from host cells, it would be important to figure out how CoVs manipulate AFs and relevant binding proteins to regulate the curvature formation of host plasma membrane.

(ii) It will be interesting to study how internalized CoVs switch transportation tracks from AFs to MTs.

(iii) Considering that the neurodevelopmental disorders and respiratory tract damage caused by CoVs are MT-dependent, it is thus of great interest to study why and how CoVs disrupt the homeostasis of MTs in infected cells.

(iv) Another key question is to understand the roles of different IF proteins in various host cells http://mc.manuscriptcentral.com/jmcb during CoV infection. Particularly, since vimentin could act as the co-receptor to be involved in the entry of SARS-CoV, it will be essential to investigate whether IF proteins function universally as a potential coronaviral (co)-receptor.

There is a substantial increase in our understanding of how host cytoskeleton network regulates CoV infection. Thorough exploration is imperative and starting now to provide new insights into cytoskeleton during CoV infections, most interestingly, from the perspective of cell biology.

Therefore, a global understanding of host cytoskeleton during CoV infection will help to inspire new strategies to control infection and relieve CoV-related pathological damage.

This study was supported by Shanghai Municipal Science and Technology Major Project 

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Feline Infectious Peritonitis: Immunohistochemical Features of Ocular Inflammation and the Distribution of Viral Antigens in Structures of

Bound virus surfs toward the foot of filopodia Li et al., 2017 (1) PEDV (α), TGEV (α)AFs line with plasma membrane for virus internalization Zhao et al., 2014 (2) HCoV-NL63 (α), HCoV-OC43 (β), PHEV (β)Virus internalization requires dynamic actin rearrangements Li et al., 2017; Milewska et al., 2018; (TGEV (α), PHEV (β)Virus hijacks actin-regulating signaling pathways to promote entry Hu et al., 2016; Lv et al., 2019 (4) MHV (β) Blocking Rac1 and Cdc42 signal transduction inhibits virus infection Koivusalo et al., 2010 (5) Knockdown of ezrin or expression of dominant-negative ezrin increases virus entry Millet et al., 2012; Millet et al., 2015 (6) SARS-CoV (β) Ezrin interacts with SARS-CoV S endodomain Millet et al., 2012 Entry PDCoV (δ) N protein of virus upregulates ezrin Lee et al., 2015 (8) PEDV (α),Actin rings support viral genome replication and viral protein synthesis Surjit et al., 2004; Gov et al., 2006; Wang et al., 2009; Zhao et al., 2014; Sun et al., 2017 (9) SARS-CoV (β)N protein induces p38 MAPK cascade and remodel actin Surjit et al., 2004; Gerits et al., 2007; Zhao et al., 2014 (10) Replication and assembly TGEV (α)The interaction of filamin A with S protein is essential for the retention of S protein at the ERGIC Trincone et al., 2015 (11) IBV (γ)The interaction between β-actin and M protein is essential for virus assembly and budding Gov et al., 2006; Wang et al., 2009 (12) Egress

Infection results in proliferation of pseudopodia and thickening of AFs at the late stage of infection Ng et al., 2004 (13) http://mc.manuscriptcentral.com/jmcb 23 The specific interaction between tau and JHMV N protein Pasick et al., 1994; Kalicharran et al., 1995 (18) LC3 acts as the cross-node of multiple pathways to take part in the formation process of DMVs Prentice et al., 2004a; Prentice et al., 2004b; Cottam et al., 2011; Reggiori et al., 2011; Maier et al., 2013 (19) Transport Syncytia MHV (β)MTs perhaps provide guidance for the transportation of GA into the center of the syncytia Kalicharran et al., 1996; Lavi et al., 1996 (31) Infection induces tau phosphorylation and disrupts MT stabilizing capacity, thereby causing brain damage Kalicharran et al., 1995; Sy et al., 2011; Barbier et al., 2019 (32) Infection restricts MT-mediated Cx43 delivery to the cell membrane via the interaction between N protein and tubulins Basu et al., 2017 (33) MHV (β)Chemical disruption of MTs significantly inhibits S protein-mediated neuronal transport and subsequent spread of RSA59 whereas RSMHV2 remains unaffected.Das Sarma et al., 2008; Das Sarma et al., 2009; Biswas et al., 2014 (34) Brain damage and cilia lossViruses cause cilia loss in the upper respiratory tract and lung, whereas low toxicity HCoV-OC43 does not affect cilia functions Chilvers et al., 2001; Nicholls et al., 2003; Villarreal et al., 2007; Priestnall et al., 2009; Mitchell et al., 2013; Essaidi-Laziosi et al., 2018; Haverkamp et al., 2018 (35) MERS-CoV (β), SARS-CoV-2 (β)The level of troponin in the heart muscle of patients is increased in infection Alhogbani, 2016; Chen et al., 2020; Guo et al., 2020; Inciardi et al., 2020; Lippi et al., 2020; Madjid et al., 2020; Shi et al., 2020 (36)

Papain-like protease induces vimentin upregulation and activation of TGF-β1 Li et al., 2012 (37) FIPV (α) Infection induces high expression of vimentin and mild expression of GFAP in astrocytes Poli et al., 1997; Mesquita et al., 2016; Ziolkowska et al., 2017 (38) Others HCoV-OC43 (β)Modifications in the phosphorylation state of neurofilaments are associated with multiple sclerosis during infection Tsunoda et al., 2002; Brison et al., 2014 (39) http://mc.manuscriptcentral.com/jmcb 26