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 cytosine–phosphate–guanosine (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 down‐regulation 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 to explain factors that contribute to the variety of clinical manifestations and outcome of SARS‐CoV‐2 infection.
SARS‐CoV‐2 subversion of innate immune responses
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, Fig. 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 the STING–TRAF3–TBK1 complex, thereby blocking STING/TBK1/IKKε‐induced type I IFN production, signal transducer and activator of transcription (STAT)‐1/2 translocation to the nucleus, IRF3, NF‐κB 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, MDA‐5 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 IFN 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) . BST2 acts by tethering budding viruses to the 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 IFN pathway. While this facilitates widespread viral replication, increasing the viral load also promotes the viral cytopathic effects leading to tissue damage described below, and probably leads to exacerbation and hyperinflammation of the innate immune response once triggered.
Triggering innate immunity
Despite immune evasion and subverting innate immune responses during early infection, SARS‐CoV‐2 effectively initiates immune signalling pathways. This is probably due to the increased viral load that exponentially produces viral RNA and viral proteins [pathogen‐associated molecular patterns (PAMPS)], and 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 . ACE2 regulates the renin–angiotensin system (RAS) by balancing the conversion of angiotensin I to angiotensins 1–9 and angiotensin II to angiotensins 1–7. Binding of SARS‐CoV‐2 to ACE2 leads to endosome formation, reducing ACE2 expression on the cell surface (Figs. 3 and 4) and pushing the RAS system to a proinflammatory mode, triggering production of reactive oxygen species (ROS), fibrosis, collagen deposition and a proinflammatory environment, including IL‐6 and IL‐8 production, by macrophages and recruitment of neutrophils (Fig. 4). Thus, binding and entry of SARS‐CoV‐2 via the ACE2 is likely to be the first step in a line of augmented and detrimental immune responses in COVID‐19 that involves complement activation, innate immune activation via PAMPS and DAMPS, inflammasome activation and pyroptosis, natural killer (NK) cell activation, hyperactivation of macrophages, neutrophils and innate T cells and induction of a cytokine storm, as discussed below
SARS‐CoV‐2 is heavily decorated with glycans (Fig. 1) that are recognized by DC‐SIGN and other lectins that facilitate viral uptake by dendritic cells (DCs). Glycans also activate the lectin complement pathway following binding of mannose‐binding protein (MBP) to SARS‐CoV‐2 viral proteins expressed on infected cells (Figs. 1 and 2). Pathology studies and transcriptional profiles of tissues from COVID‐19 cases reveal robust activation of the complement system with the deposition of MBL, C4d, C3 and C5b‐9, forming the membrane attack complex (MAC) in alveolar and epithelial cells [68, 69] (Fig. 4). In addition, C4d and C5b‐9 deposits in lung and skin microvasculature co‐localized with spike glycoproteins indicates systemic complement activation, supporting the role of complement in tissue damage . Importantly, activation of the lectin, as well as the classical pathway following antibody binding to viral proteins, probably contributes to cell damage (Fig. 4)  by either direct complement‐mediated lysis or via antibody‐dependent cell‐mediated cytotoxicity. Of relevance to the coagulation dysfunction, thrombosis and vascular damage observed following SARS‐CoV‐2 infection is that complement components induce secretion of von Willebrand factor , but also promotes monocyte and neutrophil recruitment as well as stimulating NET formation  that, in turn, perpetuates complement activation (Fig. 4). Complement may thus contribute to widespread tissue damage in SARS‐CoV‐2‐infected cases. The pathogenic role of complement in disease is supported by findings in mice. For example, mice deficient in C3 had similar viral load as wild‐type mice, but lacked the overt pathology with fewer neutrophils and macrophages in the lung . Thus, while complement activation is not required for control of virus infection it probably plays a key role in the tissue damage.
PAMPS and DAMPS mediate innate immune signalling
Infected pneumocytes and other permissible cells undergo cell damage and cell death releasing virally associated molecules, so‐called PAMPS. In addition, intracellular components released due to damage, so‐called DAMPS, include ATP, oxidized lipids, heat shock proteins and other components associated with regulated cell death programmes including apoptosis, autophagy, necroptosis and pyroptosis (Figs. 3 and 4). Thus, both DAMPS and PAMPS contribute to innate immune activation in COVID‐19.
RNA viruses trigger several Toll‐like receptors (TLRs), including TLR‐7/8 and TLR‐3, and elegant molecular in‐silico docking studies show that the spike protein of SARS‐CoV‐2 can bind to TLR‐1, TLR‐4 and TLR‐6  (Fig. 3), whereas in vitro the SARS‐CoV spike protein triggers NF‐κB activation and IL‐8 production via TLR‐2 signalling in human peripheral blood mononuclear cells (PBMCs) . In mice in which specific points in the TLR pathway were deleted; that is, TLR‐3−/−, TLR‐4−/− and TRIF‐related adaptor molecule (TRAM)−/− animals, were more susceptible to SARS‐CoV infection, although the clinical severity of disease was dramatically reduced. This was in direct contrast to deficiency in TIR‐domain‐containing adapter‐inducing IFN‐β (TRIF, the TLR adaptor protein (Fig. 3) in which TRIF−/− mice developed severe disease, exacerbated influx of macrophages and neutrophils and lung pathology indicative of COVID‐19 pathology. Thus, a balanced response to infection via the TLR‐3 pathway is essential to trigger a protective response to SARS‐CoV . This study also supports the idea that in addition, PAMPS, immune pathways triggered by DAMPS such as oxidized phospholipids, high mobility group box 1 (HMGB1), histones, heat shock proteins and adenosine triphosphate released by damaged cells may contribute to COVID‐19 outcome (Figs. 3 and 4). In addition to RIG‐I, MDA‐5 and MAVS, RNA viruses are also sensed by the STING that is activated by cGAMP when enveloped RNA viruses interact with the host membranes . Downstream, STING engages TBK1 that actives IRF3 and/or NF‐κB inducing type 1 IFN and/or proinflammatory cytokines. That hyperactivation of STING contributes to severe COVID‐19, as has been hypothesized by Berthelot and Lioté . 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 . Furthermore, STING polymorphisms are associated with ageing‐related diseases such as obesity and cardiovascular disease, possibility explaining the impact of co‐morbidities and development of severe COVID‐19 . Also, in bats, in which SARS‐CoV‐2 may have arisen, STING activation, and thus consequently IFN‐β, is blunted , probably 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 . Depending on its conformation, HMGB1 triggers TLR‐2, TLR‐4 and TLR‐9, the receptor for advanced glycation end‐products (RAGE) and triggering receptor expressed in myeloid cells 1 (TREM‐1) (Fig. 3). In mice, intratracheal administration of HMGB1 activates mitogen‐activated protein kinase (MAPK) and NF‐κB, 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 as HMGB1−/− mice display delayed coagulation, reduced thrombus formation and platelet aggregation . Furthermore, blocking HMGB1 is beneficial in experimental lung injury and sepsis, suggesting that therapies targeting HMGB1 might also be beneficial in severe COVID‐19 [83,84].
Inflammasome activation and pyroptosis
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 . Activation of the NLRP3 inflammasome, essential for effective anti‐viral immune responses, is elicited by several factors associated with SARS‐CoV infection, including RAS disbalance, engagement of PPR, TNFR and IFNAR, mitochondrial ROS production and complement components including MAC, as well as SARS‐CoV viral proteins such as ORF3a, N and E  (Fig. 3, Table 2). As a consequence, NLRP3 interaction with adaptor apoptosis speck‐like protein (ASC) recruits and activates procaspase‐1, processing pro‐IL‐1β and pro‐IL‐18 to the activated forms (Fig. 3). This drives the propyroptotic factor gasdermin D (GSDMD) formation of pores in the cell membrane; that is, 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.
Hyperinflammation and severe COVID‐19
The delayed IFN 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 monocyte–macrophages and neutrophils probably produce the first wave of tumour necrosis factor (TNF)‐α, IL‐6, IFN‐γ‐induced protein 10 (IP‐10), monocyte chemoattractant protein‐1 (MCP‐1), macrophage inflammatory protein (MIP)‐1α and regulated on activation, normal T‐expressed and secreted (RANTES) production [87, 88]. Hyperinflammation is probably promoted by co‐morbidities due to increased ACE2 expression, concurrent bacterial infections and ageing as well as a direct effect of SARS‐CoV‐2 replication, as virus–host interactome studies reveal that SARS‐CoV‐2 nsp10 regulates the NF‐κB repressor factor NKRF, facilitating IL‐8 production . This is followed by a second wave of cell recruitment, including NK cells that produce IFN‐γ and further recruitment of (alternatively activated) monocytes/macrophages and neutrophils (Fig. 4), as observed in bronchial lavages, post‐mortem tissues and peripheral blood studies [88, 89]. NK cells are key players in disease outcome of infection, critically balancing the direct response to the virus by eliminating infected cells while also augmenting tissue damage (Fig. 4). Probably aided by IFN‐γ induction by NK cells, hyperinflammation in severe COVID‐19 is also characterized by recruitment of immature and mature human monocyte‐derived DCs that harbour SARS‐CoV infection; however, infection is abortive and mature virions are not released. During infection, DCs express only low levels of cytokines probably due to innate immune subversion strategies. The sustained activation of infiltrating monocytes and monocyte‐derived macrophages  observed in severe COVID‐19 cases is probably driven by a number of factors, including oxidative stress, anti‐SARS‐CoV‐2 antibody–antigen complexes, NLRP3 inflammasome activation and complement activation that converge to sustain an aberrant hyperinflammatory response, or cytokine storm . Following SARS‐CoV‐2 infection, one of the first innate immune cells to infiltrate into the tissues are neutrophils, probably recruited by chemokine (C‐X‐C motif) ligand (CXCL)2 and CXCL8 generated by infected cells . While neutrophils do not clear viral particles, they phagocytose apoptotic bodies containing virus and debris, releasing proteolytic enzymes, anti‐microbial peptides, matrix metalloproteinases and high levels of ROS to inactivate viruses. A key function of neutrophils relevant to the pathology of SARS‐CoV‐2 is the production of neutrophil extracellular traps (NETs) generated in response to endothelial damage, ROS production, IL‐1β production and virus replication (Fig. 4, reviewed in ). The formation of NETs by neutrophils are aided by activated platelets associated with damaged endothelial cells that further activate the complement, fuelling the coagulation cascade and thrombi formation. While the NETs act to prevent further spread of the virus, they trigger platelet activation and bind erythrocytes thereby promoting (micro)thrombi formation (Fig. 4).
SARS‐CoV‐2 is a vascular and coagulation disease
While respiratory damage and complications are the major clinical signs of severe COVID‐19 many tissues and organs are affected often prior to, or independently of lung pathology, for example Kawasaki‐like vascular disease in children . Clinical, post‐mortem studies and experimental animal models of SARS‐CoV reveal infection of endothelial cells and the widespread damage of endothelial cells, vascular dysfunction and thrombosis [94, 95] that are emerging as a common pathological feature of SARS‐CoV‐2 infection. The link between SARS‐CoV‐2 infection, vascular damage and thrombosis is evidenced by high levels of D‐dimers in 20–40% critically ill patients probably produced in an attempt to dissolve thrombotic clots. The endothelial cell damage is supported by the finding that endothelial cells express ACE2 and are thus permissible to SARS‐CoV‐2 infection . Thus, infection not only leads to reduced ACE2 in endothelial cells, but also direct viral cytopathic damage and increased vascular permeability (Fig. 4), although more recent data challenge this view, suggesting that pericytes and not endothelial cells are permissible to infection and viral‐induced damage [95, 96]. Damage of endothelial cells and pericytes leads to vascular permeability in severe COVID‐19 that is probably amplified by activation of complement components widely expressed in post‐mortem tissues of COVID‐19 cases [68, 69]. Disruption of the vascular barrier and endothelial cell exposure to IL‐1β, TNF‐α and ROS increase expression of P‐selectin, von Willebrand factor (vWF) and fibrinogen, and attracting platelets that trigger expression of tissue factor (Fig. 4). Together, this sequence triggers the coagulation cascade and explains the finding of increased D‐dimer and fibrin, abnormal clotting times in severe COVID‐19 cases and widespread disseminated thrombi in post‐mortem tissues.
Disease severity, co‐morbidities and innate immunity
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 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, co‐morbidities such as cancer, immune suppression, autoimmune diseases, inflammatory disease, neurodegenerative diseases, obesity, gender and race [97-106]. For example, in a large cohort of 72 314 cases the case fatality ratio for more than 80 years was 14·8 versus 2·3% in the total cohort . This is probably higher due to inflamm‐ageing, an aberrant innate immune response such as lower production of IFN‐β , increased oxidative stress  and sensence of macrophages that become less effective in their reparative functions with age . Similarly, viral load, obesity, gender, race, blood groups and co‐morbidities have all been reported to influence the response to SARS‐CoV‐2 infection (Table 4) [101-112], 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]. Similarly, novel approaches have been put forward to target the susceptible ageing population or those with co‐morbidities. One approach under investigation is to re‐establish the youthful function of macrophages and repair mechanisms using metformin, a drug used in type II diabetes that has been shown to attenuate hallmarks of ageing . 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 , the risk in subjects taking metformin was significantly reduced (odds ratio = 0·33; 95% confidence interval = 0·13–0·84), suggesting that metformin might be protective in high‐risk populations, especially as metformin has also been reported to suppress neutrophil‐induced NETosis in vitro and reduce circulating NETosis biomarkers in vivo . Thus, metformin and other drugs such as niacin ,that rejuvenate the innate immune system, may be useful in COVID‐19.
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