key: cord-0887845-l3f12hg4
authors: Amor, Sandra; Fernández Blanco, Laura; Baker, David
title: Innate immunity during SARS‐CoV‐2: evasion strategies and activation trigger hypoxia and vascular damage
date: 2020-09-26
journal: Clin Exp Immunol
DOI: 10.1111/cei.13523
sha: 199dc2fddbc7c66bb111c4ac4b97f0ff483738b1
doc_id: 887845
cord_uid: l3f12hg4

Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS‐CoV‐2 has evolved strategies to circumvent innate immune detection including low CpG levels in the genome, glycosylation to shield essential elements including the receptor binding domain, RNA shielding and generation of viral proteins that actively impede anti‐viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS‐CoV‐2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines, and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin‐angiotensin system due to downregulation of angiotensin converting enzyme 2, the receptor for SARS‐CoV‐2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS‐CoV‐2 infection, much of which is based on the knowledge from SARS‐CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID‐19 may help explain factors that contribute to the variety of clinical manifestations and outcome of SARS‐CoV‐2 infection.

The emergence in Wuhan China of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an epidemic of the coronavirus disease 2019 (COVID- 19) . As of September 9 th 2020, the confirmed 27,761,748 cases including 902,306 deaths have been reported worldwide (worldometers.info/coronavirus). At the end of January 2020, the WHO declared COVID-19 a pandemic and a global health emergency.

The family Coronaviridae is subdivided into Torovirinae and Coronavirinae that contains the genera Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. The human coronaviruses (HCoV) belong to the αlpha-CoV (HCoV-229E and HCoV-NL63) and beta-CoV (Middle East respiratory syndrome coronavirus-MERS-CoV, SARS-CoV, HCoV-OC43

and HCoV-HKU1) [ Table 1 ; (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) ]. In comparison with most HCoVs that cause mild upper respiratory tract infections, SARS-CoV, MERS-CoV and SARS-CoV-2 induce severe pneumonia (12) . The clinical presentation of COVID-19 ranges from mild 'flu-like' symptoms to severe respiratory failure and death although between 17.9-57% of SARS-CoV-2 infections are asymptomatic depending on the population (13) . Common symptoms include fever, cough, fatigue, shortness of breath, headache and pneumonia. In addition, some patients develop gastrointestinal problems (14) , and neurological manifestations, including headache, dizziness, hyposmia and hypogeusia. Age and comorbidities i.e., hypertension, chronic obstructive pulmonary disease, diabetes, obesity and cardiovascular disease predispose to more severe manifestations, including severe respiratory failure, septic shock, coagulation dysfunction, strokes, cardiovascular problems (15) and neurological manifestations (16) .

Although the origin and transmission of SARS-CoV-2 is unclear, genome sequencing reveals marked similarities with SARS-CoV (17) . However, in comparison, SARS-CoV-2 spreads more quickly than SARS-CoV, likely due to the 10-20% fold higher in infectivity and transmissibility during the initial non-symptomatic period (4-5 days) . In some cases, transmission has been reported after development of initial symptoms despite the presence of antibodies, (18) indicating that both, neutralising antibodies and T cell responses, are necessary to prevent reinfection and for protection (19) . This is further supported by studies showing PD1 + CD57 + T cell exhaustion, depletion or inactivation is associated with viral persistence in severe cases (20) .

SARS-CoV-2 is a positive-sense RNA (29,903 nucleotides) enveloped virus of 60 to 140 nm diameter (21) . The envelope is studded with homotrimers spike proteins of 8-12 nm length that are heavily decorated with N-glycans [figure 1 (22, 23) ]. Similar to other HCoVs, SARS- 

This article is protected by copyright. All rights reserved non-structural proteins (nsp) while ORFs 2-10 encode the viral structural proteins -spike, envelope, membrane and nucleocapsid, and the accessory proteins [figure 1b]. Differences between the structural, non-structural and accessory proteins of SARS-CoV-2 and other coronaviruses help to explain the high infectivity rate and the range of pathologies observed (12, 15, 16) . While knowledge of SARS-CoV2 is rapidly emerging, parallels with SARS-CoV, as well as ongoing sequencing data and antigenic typing will be crucial to understand the dynamics of the pandemic. SARS-CoV-2 cell entry is similar to SARS-CoV being mediated by the binding of the receptor-binding domain (RBD) of the S1 protein, to the angiotensinconverting enzyme-2 (ACE-2), although other receptors such as CD147 and CD-SIGN have been reported [ Table 1 ]. Docking of the RBD to the receptor and the action of furin, a serine protease that separates the S1 and S2 proteins exposes a second binding domain on S2 allowing membrane fusion. Binding of the S protein to ACE-2 requires priming by cell proteases -primarily TMPRSS2, however, TMPRSS2 is expressed by a subset of ACE2 + cells supporting the notion that the virus likely uses other host enzymes such as TMPRSS4, lysosomal cathepsins and neuropilin-1 (24) to augment the impact of furin and expose the RDB thus promoting SARS-CoV-2 entry (11) . The structural proteins M, E and N are crucial for stability of the viral genome and viral replication. The nsp and accessory proteins (25) encoded by 10 open reading frames (ORFs) have differing functions during viral replication [Table 2 and many also act to deviate the innate immune response thus augmenting viral replication and spread. The degree to which the innate immune system is suppressed and evaded clearly determines the viral load and the host's outcome to infection, the clinical symptoms and the severity of the disease.

Following infection, viral RNA is sensed by several classes of pattern recognition receptors (PPRs). The retinoic acid-like receptors (RLRs) include retinoid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), Toll-like receptors (TLR) -classically 3, 7 and 8 that trigger IFN pathways and cytokines production [ figure 2 ]. Once engaged these PPRs act downstream via the kinases TANK-binding kinase-1 (TBK1) and inhibitor-B kinases (IKKs). Such triggering leads to the activation of the transcription factors interferonregulatory factor-3 (IRF3) and 7 (IRF7) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFB). These subsequently induce expression of type I IFNs (IFNα/β) and interferon stimulated genes (ISGs) [figure 2] many of which have potent antiviral activities, as well as other proinflammatory mediators e.g. cytokines, chemokines and antimicrobial peptides that are essential to initiate the host innate and adaptive immune response. In addition, the absent in melanoma 2 (AIM2)-like receptors and NOD-like receptors (NLRs)

This article is protected by copyright. All rights reserved trigger the inflammasome and IL-1 and IL-18 production leading to pyroptosis [ figure 2 ].

immune responses include C-type lectins and the stimulator of interferon genes (STING).

While the cGas/STING pathway is commonly associated with sensing cytosolic DNA, it is also activated following binding of enveloped viruses to host cells and cytosolic viral RNA (64, 65) .

Similar to TLRs and RLR, downstream, STING engages TBK1 to active IRF3 and/or NFB inducing type I IFN and/or proinflammatory cytokines [ figure 2 ].

Coronaviruses have evolved several strategies to escape such innate immune recognition allowing widespread replication. Such evasion includes evolution of low genomic CpG, RNA shielding, masking of potential key antigenic epitopes as well as inhibition of steps in the interferon type I/III pathways. Generally, the zinc finger antiviral protein (ZAP) specifically binds to and degrades CpG motifs in genomes of RNA viruses. In comparison with other viruses, SARS-CoV-2 has evolved the most extreme CpG deficiency of all betacoronavirus [ (26) . Another strategy to protect mRNA used by the host and many viruses is the processing of capping the 5′ end. For both host and virus RNA, capping limits degradation and importantly blocks recognition by cytosolic PPRs. Like many RNA viruses SARS-CoV-2 has exploited several mechanisms to protect the 5′ ends by a cap structure of RNA generated during replication. While some viruses snatch the caps from host RNA, SARS-CoV-2, like other coronaviruses uses its own capping machinery composed of nsp10, nsp13 and the 

This article is protected by copyright. All rights reserved proteins of 8-12 nm length that are heavily decorated with glycans. Each spike protein comprises of two subunits (S1 and S2) that each bear 22 glycan groups (49) . Cell entry of the highly glycosylated S protein of SARS-CoV is promoted by DC-SIGN possibly augmenting virus uptake or aiding capture and transmission of SARS-CoV by DCs and macrophages (6) (7) (8) .

Similar to the spike protein, the other structural, non-structural and accessory proteins are also modified by glycosylation, palmitoylation, phosphorylation, SUMOylation and ADPribosylation (67) . Conversely, some viral proteins e.g. nsp3, possess deubiquitinating (DUB) and deISGylation activity thereby interfering with host functions targetting those that are critical for signalling transduction of innate immunity (34) . Insertion of the spike protein into cell membranes during replication is a key step for virus budding. Whilst this takes place in the RTC [suppl figure 1 ], receptor-bound spike proteins interact with TMPRSS2 expressed on the uninfected cell surface, mediates fusion between infected and uninfected cells promoting the formation of syncytia allowing the virus to spread to adjacent uninfected cells while evading detection by the immune response (68) .

In addition to strategies to evade PPR recognition, SARS-CoV-2 has also evolved strategies to inhibit steps in the pathway leading to type I/III IFN production. This may be especially relevant in the lungs where type IFN III (lambda) is considered to be more effective in controlling viral infections and critically affected in COVID-19. Knowledge arising from the study of other coronaviruses, especially SARS-CoV and MERS, has shown that many of the non-structural, structural and accessory proteins interfere with elements of the IFN pathway [ Table 2 , figure 2 ], essential for the development of effective immunity. IFN antagonism has been attributed to several of the structural, non-structural and accessory proteins that interfere with stimulator of interferon genes (STING)-TRAF3-TBK1 complex, thereby blocking STING/TBK1/IKKε-induced type I IFN production, STAT-1/2 translocation to the nucleus, IRF3, NFB signalling as well as interfering with the actions of the ISG products including IFITs [ Table 2 ]. As examples, nsp1, 4 and 6, and ORF6 interfere with STAT-1/2 signalling while nsp 10, 13 and 16 cap the viral RNA [ Table 2 ] preventing recognition by RIG-I, MDA5

and IFITs. Nsp3 also acts by DUB proteins thereby preventing their activity such as RIG-I and other steps in the IFN pathways for which ubiquitination is essential. CoV PLPro (nsp 3) also interrupts the stimulator of interferon genes STING.TRAF3. TBK1 complex thereby blocking STING/TBK1/IKKε-type I IFN production (32, 34) . As well as subversion of the IFN pathway, SARS-CoV ORF7a (also present in SARS-CoV-2) blocks the activity of tetherin also known as bone marrow stromal antigen 2 (BST-2) (58). BST2 acts by tethering budding viruses to the

This article is protected by copyright. All rights reserved cell membrane thus preventing its release from the cells. ORF7a removes this inhibition aiding the release of mature virions.

In summary, emerging evidence from SARS-CoV-2, and comparison with other SARS-Cov and MERS, reveals many strategies used to evade the innate immune response and subvert the interferon pathway. While this facilitates widespread viral replication increasing the viral load also promotes the viral cytopathic effects leading to tissue damage described below, likely leads to exacerbation and hyperinflammation of the innate immune response once triggered.

Despite immune evasion and subverting innate immune responses during early infection, SARS-CoV-2 effectively initiates immune signalling pathways. This is likely due to the increased viral load that exponentially produces viral RNA and viral proteins (pathogen associated molecular patterns -PAMPS), also induces cell damage that release damage associated molecular patterns (DAMPS) both of which trigger innate immune pathways.

Like SARS-CoV and NL63, SARS-CoV-2 uses the angiotensin (Ang)-converting enzyme-2 (ACE2) as a cell receptor [ Table 1 ], expressed on epithelia in renal, cardiovascular and gastrointestinal tract tissues, testes and on pneumocytes and vascular endothelia (66) . ACE2 regulates the renin-angiotensin system (RAS) by balancing the conversion of angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7. Binding of SARS-CoV-2 to ACE2 leads to endosome formation, reducing ACE2 expression on the cell surface [figures 3 and 4] and pushing the RAS system to a pro-inflammatory mode triggering production of reactive oxygen species, fibrosis, collagen deposition and a proinflammatory environment including IL-6 and a balanced response to infection via TLR3 pathway is essential to trigger a protective response to SARS-CoV (76) . This study also supports the idea that in addition, PAMPS,

This article is protected by copyright. All rights reserved immune pathways triggered by DAMPS such as oxidised phospholipids, high mobility group box 1 (HMGB1), histones, heat shock proteins and adenosine triphosphate released by damaged cells may contribute to COVID-19 outcome [figures 3 and 4] . In addition to RIG-I, MDA5 and MAVS, RNA viruses are also sensed by the stimulator of interferon genes (STING) that is activated by cGAMP when enveloped RNA viruses interact with the host membranes (64) . Downstream, STING engages TBK1 that actives IRF3 and/or NFB inducing type 1 IFN and/or proinflammatory cytokines. That hyperactivation of STING contributes to severe COVID-19 as has been hypothesised by Berthelot and Lioté (77) . These authors present several lines of evidence, the strongest being that gain of function mutations of STING associated with hyperactivation of type I IFN induces the disease SAVI (STING-Associated Vasculopathy with onset in Infancy). Affected children with SAVI present with pulmonary inflammation, vasculitis and endothelial-cell dysfunction that mimics many aspects of COVID-19 (78) . Furthermore, STING polymorphisms are associated with ageing-related diseases such as obesity and cardiovascular disease, possibility explaining the impact of comorbidities and development of severe COVID-19 (78) . Also, in bats in which SARS-CoV-2 may have arisen, STING activation and thus consequently IFN is blunted (79), likely aiding viral replication and spread as observed in early SARS-CoV-2 infection in humans. That DAMPS released due to viral cytotoxicity may contribute to severe COVID-19 which is best exemplified by HMBG1 released by damaged and dying cells as well as activated innate immune cells especially in sepsis (80) . Depending on its conformation HMGB1 triggers TLR2, TLR4 and TLR9, the receptor for advanced glycation end-products (RAGE) and triggering receptor expressed in myeloid cells 1 (TREM-1) [ figure 3 ]. In mice, intratracheal administration of HMGB1 activates mitogen-activated protein kinase (MAPK) and NFκB, inducing proinflammatory cytokines, activating the endothelium and recruiting neutrophils in the lung -key pathological features of severe COVID-19 (80, 81) . HMGB1, and especially the platelet-derived source may play a crucial role in SARS-CoV-2 vascular damage since HMGB1 -/mice display delayed coagulation, reduced thrombus formation and platelet aggregation (82) . Furthermore, blocking HMGB1 is beneficial in experimental lung injury and sepsis, suggesting therapies targeting HMGB1 might also be beneficial in severe COVID-19 (83) .

Studies of peripheral blood and post-mortem tissues from severe COVID-19 cases reveal high levels of IL-1β and IL-6 and increased numbers of CD14+IL-1β monocytes, suggesting activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway (84) . Activation of the NLRP3 inflammasome, essential for effective antiviral immune responses, is elicited by several factors associated with SARS-CoV infection including RAS

This article is protected by copyright. All rights reserved disbalance, engagement of PPR, TNFR and IFNAR, mitochondrial ROS production, complement components including MAC, as well as SARS-CoV viral proteins such as ORF3a, N and E [figure 3, Table 2 ]. As a consequence, NLRP3 interaction with adaptor apoptosis specklike protein (ASC) recruits and activates procaspase-1, processing pro-IL-1β and pro-IL-18 to the activate forms [ figure 3 ]. This drives the propyroptotic factor gasdermin D (GSDMD) formation of pores in the cell membrane, i.e. pyroptosis that facilitates the release of proinflammatory cytokines. The pores also aid the release of cellular DAMPS such as HMGB1, and viral PAMPS that further exacerbate inflammation suggesting that targeting the NLRP3 pathway might be beneficial in severe COVID-19 cases.

The delayed interferon response, increased viral load and virus dissemination, coupled with the release of DAMPS and PAMPs lead to activation of several innate immune pathways.

Following infection, pneumocytes, epithelial and alveolar cells, and infiltrating monocytemacrophages and neutrophils likely produce the first wave of TNFα, IL-6, IP-10, MCP-1, MIP-1 and RANTES production (87, 88) . Hyperinflammation is likely promoted by comorbidities due to increased ACE2 expression, concurrent bacterial infections and ageing as well as a direct effect of SARS-CoV-2 replication since virus-host interactome studies reveal that SARS-CoV-2 nsp10 regulates the NFB repressor factor NKRF, facilitating IL-8 production (89). This is followed by a second wave of cell recruitment including NK cells that produce IFN and further recruitment of (alternatively activated) monocytes/macrophages and neutrophils 

SARS-CoV-2 exploits many strategies to subvert innate immune responses allowing the virus to replicate and disseminate within the host. The extent to which the virus replicates within

This article is protected by copyright. All rights reserved the host, and the efficacy of the host innate immune response to eradicate the infection and trigger effective adaptive immune responses, but not hyper-responsiveness of innate immunity, strongly determines the disease outcome [ Table 3 ]. The severity of infection has been linked to age, smoking, comorbidities such as cancer, immune suppression, autoimmune diseases, inflammatory disease, neurodegenerative diseases, obesity, gender and race (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) . For example, in a large cohort of 72,314 cases the case fatality ratio for over 80 years was 14.8% versus 2.3% in the total cohort (97) . This is likely higher due to inflamm-ageing, an aberrant innate immune response such as lower production of IFNβ (98), increased oxidative stress (99) and sensence of macrophages that become less effective in their reparative functions with age (100). Likewise, viral load, obesity, gender, race, blood groups and comorbidities have all been reported to influence the response to SARS-CoV-2 infection, [ Table 4 ; (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) (112) ] although few studies have fully examined the extent to which subversion and activation of innate immune components contribute to susceptibility in these cases.

Understanding the innate immune factors that exacerbate the vascular complications will be crucial to control severe disease following SARS-CoV-2 infection. Rapidly emerging studies reveal the extent to which therapeutic approaches for other viral infections and inflammatory diseases can be repurposed to target innate immunity to treat COVID-19 patients (113, 114) .

Likewise, novel approaches have been put forward to target the susceptible ageing population or those with comorbidities. One approach under investigation is to re-establish the youthful function of macrophages and repair mechanisms using metformin, a drug used in type 2 diabetes that has been shown to attenuate hallmarks of ageing (115) . In a retrospective study of 25,326 subjects tested for COVID-19 while diabetes was reported to be an independent risk factor for COVID-19-related mortality (116) 

This article is protected by copyright. All rights reserved UPR -unfolded protein response; ZAP -zinc finger antiviral protein.

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved (B) and hyperinflammation with influx of macrophages, NK cells and neutrophils (C). This self-augmenting cycle triggers further cell damage and DAMPS and PAMPs release as well as ROS production. D) Activation of neutrophils induces neutrophil extracellular traps (NET) aided by the N protein and generated in response to ROS-induced endothelial cell damage.

Disruption of the vascular barrier and endothelial cell exposure to proinflammatory cytokine and ROS increases expression of P-selectin, von Willebrand factor (vWF) and fibrinogen, that attract platelets triggering expression of tissue factor. Together this sequence activates the complement system, one of many pathways that crucially activates the coagulation cascade leading to thrombi formation. 

Human aminopeptidase N is a receptor for human coronavirus 229E

TMPRSS2 Activates the Human Coronavirus 229E for Cathepsin-Independent Host Cell Entry and Is Expressed in Viral Target Cells in the Respiratory Epithelium

Infection of primary cultures of human neural cells by human coronaviruses 229E and OC43

HLA Class I Antigen Serves as a Receptor for Human Coronavirus OC43

Human and bovine coronaviruses recognize sialic acid-containing receptors similar to those of influenza C viruses

DC-SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the S Protein of Severe Acute Respiratory Syndrome Coronavirus

CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus

Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry

Identification of Major Histocompatibility Complex Class I C Molecule as an Attachment Factor That Facilitates Coronavirus HKU1 Spike-Mediated Infection

Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein

A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Clinical and immunologic features in severe and moderate Coronavirus Disease

Asymptomatic carriage and transmission of SARS-CoV-2: What do we know?

Gastrointestinal involvement in COVID-19: a systematic review and meta-analysis

Description and Proposed Management of Accepted Article This article is protected by copyright. All rights reserved the Acute COVID-19 Cardiovascular Syndrome

Neurological associations of COVID-19

The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

Targets of T Cell Responses to SARS-CoV-2

Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

3D Models of glycosylated SARS-CoV-2 spike protein suggest challenges and opportunities for vaccine development

Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy

Neuropilin-1 is a host factor for SARS-CoV-2 infection

Accessory proteins of SARS-CoV and other coronaviruses

Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense

Identification of Residues of SARS-CoV nsp1 That Differentially Affect Inhibition of Gene Expression and Antiviral Signaling

Severe Acute Respiratory Syndrome Coronavirus Evades Antiviral Signaling: Role of nsp1 and Rational Design of an Attenuated Strain

Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation

The nsp2 Replicase Proteins of Accepted Article This article is protected by copyright

Murine Hepatitis Virus and Severe Acute Respiratory Syndrome Coronavirus Are Dispensable for Viral Replication

Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling

The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds

Severe Acute Respiratory Syndrome Coronavirus Nonstructural Proteins 3, 4, and 6 Induce Double-Membrane Vesicles

SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex

Severe acute respiratory syndrome coronavirus 3C-like protease-induced apoptosis

Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors

The nsp9 replicase protein of SARS-coronavirus, structure and functional insights

The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world

Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex

The interaction of the SARS coronavirus non-structural protein 10 with the cellular oxido-reductase system causes an extensive cytopathic effect

Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex

Multiple Enzymatic Activities Associated with Severe Acute Respiratory Syndrome Coronavirus Helicase

Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis

Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages

Attenuation and Restoration of Severe Acute Respiratory Syndrome Coronavirus Mutant Lacking 2'-O-Methyltransferase Activity

Coronavirus non-structural protein 16: Evasion, attenuation, and possible treatments

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice

Site-specific glycan analysis of the SARS-CoV-2 spike

Severe acute respiratory syndrome coronavirus Orf3a protein interacts with caveolin

This article is protected by copyright

Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference

SARS coronavirus 7a protein blocks cell cycle progression at G0/G1 phase via the cyclin D3/pRb pathway

The ORF7b Protein of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Is Expressed in Virus-Infected Cells and Incorporated into SARS-CoV Particles

The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I. bioRxiv

The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination

SARS-Coronavirus Open Reading Frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome

The cGAS-STING Defense Pathway and Its Counteraction by Viruses

The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

Post-translational modifications of coronavirus proteins: roles and function

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Cell entry mechanisms of SARS-CoV-2

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Identification of Immune complement function as a determinant of adverse SARS-CoV-2 infection outcome. medRxiv

Mannose-Binding Lectin in Severe Acute Respiratory Syndrome Coronavirus Infection

Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface

NETosis, complement, and coagulation: a triangular relationship

Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis

In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs

SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-κB pathway in human monocyte macrophages in vitro

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

COVID-19 as a STING disorder with delayed over-secretion of interferon-beta

Activated STING in a Vascular and Pulmonary Syndrome

Dampened STING-Dependent Interferon Activation in Bats

Pathogenic role of HMGB1 in SARS? Med Hypotheses

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

Platelet-derived HMGB1 is a critical mediator of thrombosis

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19

Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome

Accepted Article This article is protected by copyright. All rights reserved

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients

Host-Viral Infection Maps Reveal Signatures of Severe COVID-19 Patients

Virus-host interactome and proteomic survey of PBMCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis

Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression

Endothelial cell infection and endotheliitis in COVID-19

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 -implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients. bioRxiv

Pericyte alteration sheds light on micro-vasculopathy in COVID-19 infection

Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China

Reduced dynamic range of antiviral innate immune responses in aging

Oxidative stress, inflamm-aging and immunosenescence

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

Metabolic Alterations in Aging Macrophages: Ingredients for Inflammaging?

Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2

ABO blood group is a determinant of von Willebrand factor protein levels in human pulmonary endothelial cells

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

COVID-19 and cancer: what we know so far

COVID-19 and diabetes mellitus: An unholy interaction of two pandemics

Impact of sex and gender on COVID-19 outcomes in Europe

Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes

Ethnic and socioeconomic differences in SARS-CoV-2 infection: prospective cohort study using UK Biobank

Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: Ethnic differences and potential new targets for therapeutic drugs

Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen

Dysregulation of Natural Killer Cells in Obesity

Prevention and treatment of COIVID-19 by control of innate immunity

Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2'-O-Methylation of Viral RNA

Benefits of Metformin in Attenuating the Hallmarks of Aging

Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. medRxiv

The antidiabetic drug metformin blunts NETosis in

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved Accepted Article