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.
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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. 