key: cord-0830876-5zxw4749 authors: Polycarpou, Anastasia; Howard, Mark; Farrar, Conrad A; Greenlaw, Roseanna; Fanelli, Giorgia; Wallis, Russell; Klavinskis, Linda S; Sacks, Steven title: Rationale for targeting Complement in COVID‐19 date: 2020-06-19 journal: EMBO Mol Med DOI: 10.15252/emmm.202012642 sha: 501cacc32f36759c08bceffdab3a52d7af2e5a07 doc_id: 830876 cord_uid: 5zxw4749 A novel coronavirus, SARS‐CoV‐2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID‐19 caused by SARS‐CoV‐2 is associated with an acute respiratory illness that varies from mild to the life‐threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro‐inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID‐19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS‐CoV‐2 immunopathogenesis and the preceding literature on SARS‐CoV‐1 and MERS‐CoV infection linking severe COVID‐19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti‐inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available. Complement has evolved as a major defence against infection, evident by the fact that many microorganisms including bacteria and viruses have developed resistance to complement and can exploit the complement system to facilitate tissue invasion (reviewed in (Agrawal, Nawadkar et al., 2017) ). The inflammatory response to infection mediated by complement may also be tissue-destructive and contribute to the clinical syndrome of sepsis (reviewed by (Rittirsch, Flierl et al., 2008) ) and multiorgan failure (MOF) (reviewed by (Rittirsch, Redl et al., 2012) ). A tipping point occurs where the harmful effects of complement in the response to infection may outweigh the beneficial effects. This is highly pertinent in COVID-19 infection, in which the highest mortality is of glycan signatures (Shajahan, Supekar et al., 2020 , Watanabe, Allen et al., 2020 (Fig 2) . The SARS-CoV-2 S gene encodes 22 N-linked glycan sequons per protomer leading to an array of host-derived glycans with each trimer displaying 66 N-linked glycosylation sites (Watanabe et al., 2020) . By analogy with SARS-CoV-1, the M protein has a critical function in the trafficking and assembly of proteins incorporated into the virion (Siu, Teoh et al., 2008 , Ye & Hogue, 2007 , being necessary for binding and packaging of the ribonucleoprotein complex and interaction with the structural proteins in virus budding (McBride, van Zyl et al., 2014) . The N protein also plays a wider role in deregulating host cell function, via antagonism of interferon  production (Kopecky-Bromberg, Martinez-Sobrido et al., 2007) , modulation of the cell cycle regulation (Surjit, Kumar et al., 2005) and host translational shutoff (Zhou, Liu et al., 2008) that taken together may contribute to disease pathogenesis. SARS-CoV-2, like SARS-CoV-1, utilises angiotensin-converting enzyme 2 (ACE2) as an entry receptor (Hoffmann et al., 2020) , which suggests SARS-CoV-2 shares a similar tropism for alveolar type II epithelial cells and possibly resident alveolar macrophages that express this receptor. The binding of the S glycoprotein to ACE2 downregulates the receptor and increases production of Angiotensin II which stimulates type 1A angiotensin receptor (AGTR1A) (Imai, Kuba et al., 2005) . This increases pulmonary vascular permeability and lung pathology (Imai et al., 2005) . ACE2 is also expressed by a minimal percentage of peripheral blood monocytes (Jiang, Xu et al., 2005) . However, whether SARS-CoV-2 directly infects any innate immune leukocytes remains unknown. This article is protected by copyright. All rights reserved It is highly possible that SARS-CoV-2 may co-opt other entry receptors or may employ other modes of cellular entry, such as antibody-dependent enhancement (ADE). For example, ADE may occur through the binding of virus-antibody immune complexes on Fc receptors or complement receptors or alternatively, by inducing a conformational change in envelope glycoproteins required for virus-cell membrane fusion (reviewed by (Tirado & Yoon, 2003) ). Moreover, SARS-CoV-2, like SARS-CoV-1, may interact with the Dendritic Cell-Specific Intercellular adhesion molecule-Grabbing Nonintegrin (DC-SIGN), a C-type lectin present on myeloid dendritic cells (DCs), and the related protein DC-SIGNR (also termed L-SIGN) (Jeffers, Tusell et al., 2004 , Marzi, Gramberg et al., 2004 , Yang, Huang et al., 2004 . It is well established that these cell surface receptors engage carbohydrate ligands expressed by several viruses and by that mechanism enhance host cell entry and infection (Grove & Marsh, 2011 , Mitchell, Fadden et al., 2001 . DCs are reported to transfer the SARS-CoV-1 to other susceptible target cells through a synapse-like structure (Yang et al., 2004) . Through this direct mechanism DCs may act as a viral reservoir that may contribute to the chronicity of this infection (Yang et al., 2004) . A recent study from Wang et al has shown that SARS-CoV-2 is able to directly infect T cells through the S glycoprotein (Wang, Xu et al., 2020) . Other receptors expressed on the surface of T cells, such as CD147, could mediate viral entry (Chen, . Lymphopenia in COVID-19 patients could also be explained by the high levels of the programmed cell death protein 1 (PD-1) on CD8 + T cells (Moon, 2020) , which is known to trigger T cell exhaustion (Jiang, Li et al., 2015) . The finding that severe cases of COVID-19 are less common in young children (Dong, Mo et al., 2020) , while this age group exhibit highly effective innate immune responses (Nikolich-Zugich, 2018) , strongly suggests the crucial role of innate immunity in this disease. However, although the innate immune system can play an important protective role against invading pathogens (Takeuchi & Akira, 2009) , when this response is over expressed it can contribute to immune mediated pathology in virus infections (Henderson, Canna et al., 2020 , Thiel & Weber, 2008 . For example, disease severity has been reported to increase during SARS-CoV-1 infection in the context of decreasing viral load (Peiris, Chu et al., 2003) . By analogy to SARS-CoV-1 (Gu, Gong et al., 2005) , This article is protected by copyright. All rights reserved infection by SARS-CoV-2 is also characterised by neutrophilia, lymphopenia and hypercytokinemia (Bermejo-Martin, Almansa et al., 2020 , Mendez, Menendez et al., 2019 . This "cytokine storm" induced by viral infection can then elicit inflammatory-induced lung injury (Huang, Wang et al., 2020) . A group of cytokines and chemokines have been associated in the literature with different coronaviral infections (IL-5, IL-6, IL-12, IFN-, G-CSF, CXCL1, MCP1, TNF-), or specifically to SARC-CoV-2 (IL-1, IL-2, IL-6, IL-8, IL-10, IL-17, IP10, MCP1, TNF-) (Huang et al., 2020 , Qin, Zhou et al., 2020 , Xu, Chen et al., 2020 . It is believed that the pathogenetic mechanism might involve a delayed type I interferon (IFN) production, resulting in the loss of viral control in the early phase of infection and influx of inflammatory immune cells, including monocytes/macrophages that hyper-produce pro-inflammatory cytokines in a similar way to SARS-CoV-1 (Yoshikawa, Hill et al., 2009 ). Added to this, comorbidities such as hypertension, diabetes, obesity, cardiovascular and respiratory diseases, have all been associated with COVID-19 severity and lethality . Pre-existing inflammation and hypoxia associated with certain conditions can predispose the respiratory tract to viral infections (Amin, El Basha et al., 2013 , Furuta, Hasegawa et al., 2018 , Kapur, Mackay et al., 2014 . The complement system is a major part of innate immunity and comprises a cascade of proteins that directly or indirectly destroy invading organisms and damaged cells, and interacts with the adaptive immune system (Turnberg & Botto, 2003) . Activation of the complement system causes C3b -the large split fragment of the central component C3to deposit on the activating surface. C3b-opsonised cells can be removed by the phagocytic system or C3b may lead to the cleavage of C5 and to the formation of the membrane attack complex (MAC) C5b-9, which results in cell injury and cell death. In addition, the small biologically active fragments C3a and C5a are anaphylatoxins, which recruit and activate leucocytes to promote inflammation. Complement activation occurs by three main routes, the classical, lectin and alternative pathways, all of which converge on C3 (Fig 3a) . The classical pathway uses the pattern recognition molecule (PRM) C1q that detects bound antibody or other immune This article is protected by copyright. All rights reserved surveillance molecules, such as C-reactive protein. The lectin pathway uses a diverse set of PRMs including collectins and ficolins, which recognize carbohydrate structures on pathogens or injured host cells (reviewed in . In contrast, the alternative pathway lacks a specific PRM but it can greatly amplify the amount of C3b formed by the classical or lectin pathways (reviewed by (Lachmann, 2018) ). Direct hydrolysis of C3 may also trigger the alternative pathway. The lectin pathway of complement is the most recent complement activation pathway to be described and is of particular interest in the setting of viral infection (Matsushita & Fujita, 1992) . The pathway starts with ligand recognition by lectins known as collectins (e.g. mannose binding lectin [MBL] ; collectin-10 [CL-10] and collectin-11 ) and ficolins (FCN 1, 2 and 3). The basic structures of these soluble collectins include a globular trimeric carbohydrate-recognition domain (CRD) and a collagen-like tail with a binding site for MBL-associated serine proteases (MASPs 1,2 and 3) (Fig 3b) . Ficolin structures, on the other hand, feature a trimeric fibrinogen-like CRD and a collagen-like tail, which also binds to MASPs 1, 2 and 3 (Fig 3b) . The lectin subunits form oligomers with increased avidity for ligand binding. These mammalian lectins differ in their preferred carbohydrate ligand, MBL, for example, binding with higher avidity to GlcNAc and Dmannose while CL-11 has a higher avidity for L-fucose and D-mannose (Weis, Drickamer et al., 1992) . Recognition of the preferred carbohydrate causes the lectin-MASP complex to initiate complement activation by cleavage of C3. Of the three essential MASPs, only MASP-2 has been shown to directly cleave C3. The lectin-MASP complex can also directly stimulate alternative pathway activation (Iwaki, Kanno et al., 2011) . These lectins are involved in a range of immune functions including viral neutralisation and clearance and promotion of inflammation through complement dependent mechanisms and also by independent mechanisms that include calreticulin receptor binding (Kishore, Greenhough et al., 2006 , Nayak, Dodagatta-Marri et al., 2012 . A distinction can be made between the role of locally synthesised complement and that of the circulating pool secreted mainly by hepatocytes (Sacks & Zhou, 2012) . Studies on C3 and CL-11 produced within the kidney mainly by tubule epithelial cells have shown marked contribution to renal inflammatory injury, whereas the contribution of systemic This article is protected by copyright. All rights reserved components was negligible (Farrar, Zhou et al., 2006 , Farrar, Zhou et al., 2016 , Pratt, Basheer et al., 2002 . In fact, many organs and cell types, including lung alveolar and bronchial epithelial cells as well as infiltrating leucocytes, produce a range of complement components despite these tissues being bathed in an abundant circulating pool (reviewed in Nauser, Howard et al., 2018) . The reason for this local synthesis is unclear, although it could be because the large molecular size of proteins such as C3 (180kDa) and C5 as well as the classical/lectin pathway constituents C4 and C2 (Pandya & Wilkes, 2014 , Strunk, Eidlen et al., 1988 . Bronchial epithelium is another source of the pivotal component C3 (Varsano, Kaminsky et al., 2000) . It may be helpful to regard MBL as a guardian of the circulation whereas other lectins like CL-11 and FCN-1 are located at epithelial surfaces too. Within the vascular compartment, complement activation can promote endothelial injury and thrombosis. While this has largely been attributed to classical pathway (antibodymediated) activation, a role for the lectin pathway of complement activation has recently come to attention. MASP-2 has been shown to cleave pro-thrombin to generate thrombin (Krarup, Wallis et al., 2007) , a serine protease that leads to the conversion of fibrinogen to fibrin -essential for clot formation. MASP-1 behaves like thrombin in that it cleaves factor VIII and fibrinogen as well as thrombin activatable fibrinolysis inhibitor (TAFI) . Furthermore both MBL-MASP and ficolin-MASP complexes bound to glycan ligand can generate a blood clot similar to those generated by thrombin when provided with factor VIII and fibrinogen (Gulla, Gupta et al., 2010) . In this way This article is protected by copyright. All rights reserved ligand recognition by the lectin complement pathway can signal to the coagulation pathway, linking these two arms of innate immunity (Fig 3a) . The finding of elevated levels of CL-11 in hypercoagulable states could underpin this ability to trigger coagulation in severely ill patients (Takahashi, Ohtani et al., 2014) , as we shall now discuss. Complement activation is a common if not fixed feature of ARDS associated with infectious and non-infectious causes. Characteristically C5a is elevated in peripheral blood samples and has been proposed as a marker of ARDS associated with severe sepsis, cytokine storm and multiorgan failure (MOF) (Hammerschmidt, Weaver et al., 1980) . Polymorphonuclear neutrophil (PMN) aggregation within the injured lung predisposes towards the development of ARDS, coinciding with increase in the levels of C5a (Hammerschmidt et al., 1980) . Furthermore, PMN exposed to activated C5a can adhere to and damage the vascular epithelium, leading to increased vascular permeability and the genesis of ARDS (Hammerschmidt et al., 1980) . This is an important observation as it may explain the neutrophilia that has also been described during COVID-19 ). derived macrophages through production of IL-6 and TNF-α can enhance cell susceptibility to infection by certain viruses. (Kacani, Banki et al., 2001) . Cytokine release through excessive C5aR1 signalling on pro-inflammatory macrophages and other leucocytes is thought to contribute to the cytokine storm associated with sepsis and MOF. This article is protected by copyright. All rights reserved Furthermore, blockade of complement anaphylatoxin C5a in experimental sepsis virtually prevents the appearance of MOF and improves the outcome (Rittirsch et al., 2008) . It is a common observation that chronic cardiopulmonary conditions predispose to severe COVID-19. One theory is that hypoxia in these conditions is a stimulant to complement activation. A rabbit model of ARDS examined the impact of hypoxia (Nuytinck, Goris et al., 1986) . It showed that the combination of hypoxia and activated complement components caused aggregation and degranulation of neutrophils, with consequent lysis and extensive microvascular damage. The characteristic microvascular inflammation and MOF in these animals signified the potent effect of this combination in the pathogenesis of ARDS Recent research has shown that SARS-CoV-2 S protein is heavily glycosylated with residues that are rich in L-fucose or D-mannose (Walls et al., 2020, Watanabe et al., 2020) (Fig 2) . suggest that more than one pattern of lung injury can occur, though at this stage additional lung biopsy data is needed to support the post-mortem findings. In addition, there have been recent reports in small groups of children with COVID-19 with aggressive multiorgan disease and laboratory evidence of hyper-inflammatory disease and thrombosis (Riphagen, Gomez et al., 2020 , Verdoni, Mazza et al., 2020 . Vasculitic lesions and hypercoagulability in these children is strongly suggestive of complement involvement through co-triggering of the complement and coagulation cascades. It is tempting to suggest that alveolar epithelium is the primary site of complement activation following exposure to SARS-CoV-2 (Fig 4) . This article is protected by copyright. All rights reserved the proximal tubule segments. The proximal tubule epithelial cell is also a prominent local source of CL-11 and other complement components known to participate in AKI (Farrar et al 2016) . Angiotensin-converting enzyme, another product of the proximal tubule epithelium, can directly cleave C3 to precipitate complement activation by another route (Semis, Gugiu et al., 2019) . Complement control could therefore have a protective effect on some or all of these processes. Earlier research on the SARS-CoV-1 and MERS-CoV viruses has provided additional insight into the complement pathways triggered by pathogenic human coronaviruses. Following the SARS-CoV-1 outbreak, a number of research groups looked at MBL as a mediator of pathology, with conflicting results (Ip, Chan et al., 2005 , Yuan, Tanner et al., 2005 . The low expression variant of MBL was reported as a susceptibility factor for SARS-CoV-1 infection (Ip et al., 2005 , Tu, Chong et al., 2015 , Zhang, Zhou et al., 2005 . Among these, the study of Tu et al included 932 patients with SARS, which accounted for 12% of the SARS worldwide (Tu et al., 2015) . A study on SARS-CoV-1 demonstrated that the SARS S glycoprotein interacts with MBL at a single asparagine-linked glycosylation site (Zhou, Lu et al., 2010) , while deposition of complement C4 on SARS-CoV-1 was enhanced by MBL (Ip et al., 2005) . On the contrary, it was demonstrated by other studies that the S glycoprotein did not bind to MBL (Leth-Larsen, Zhong et al., 2007) . In another animal model, namely chicken coronavirus infectious bronchitis virus (IBV), the antiviral activity of chicken MBL was exhibited through its binding to the spike S1 glycoprotein of the virus by its CRD in a Ca 2+ dependent manner (Zhang, Bouwman et al., 2017) . The comparative study by Gao and colleagues examined the N proteins of SARS-CoV-1, Their pre-print reported direct binding of the N proteins to MASP-2, the key serine protease of the lectin pathway. MASP-2 cleaves the complement components C4 and C2 to generate C3 convertase (Farrar et al., 2016) ; MASP-2 can also directly cleave C3 (Schwaeble, Lynch et al., 2011) . They demonstrated that this enzymatic activity of MASP-2 was enhanced in the presence of N-protein (Gao et al., 2020) . These findings, if confirmed, would suggest that pattern recognition of viral glycoproteins is important for inducing over-activity of the downstream inflammatory response mediated by the lectin pathway, and also highlight MASP-2 as a potential therapeutic target that is physically associated with all of the major collectins. Current mouse models offer limited value for investigating SARS-CoV-2 infection. This is because murine ACE2, the principal receptor for the virus, does not have a high degree of homology with the human ACE2 which binds successfully to SARS-CoV-2 . Thus, infectivity studies using HeLa cells that expressed or not ACE2 proteins from humans, Chinese horseshoe bats, civets, pigs and mice showed that SARS-CoV-2 is able to use all but the murine ACE2 proteins . Nonetheless, research with SARS-CoV-1, which binds to a higher extent the murine ACE2, has shown that nasally infected mice develop complement activation in the lung, whereas complement C3 deficient mice were protected from virus-induced lung injury A murine study on MERS-CoV emphasized that excessive complement activation may contribute to acute lung injury after infection, while blockade of the complement C5a-C5a receptor axis alleviated the lung damage (Jiang, Zhao et al., 2018) . Anti-C5aR1 antibody treatment in infected mice even led to decreased pulmonary viral replication (Jiang et al., 2018) . These findings were reflected in an early report of an ongoing clinical study, where two COVID-19 patients with ARDS began to improve only after treatment with recombinant anti-C5a antibody (Gao et al., 2020) . With the accumulation of data supporting an excessive inflammatory response, in part due to over activation of the complement system, attention has turned to the potential use This article is protected by copyright. All rights reserved of therapeutic complement inhibitors that are on the market and in various stages of development (Table 1) . For a comprehensive list of complement therapies see publication by Zelek et al (Zelek, Xie et al., 2019) . Amongst these are antibodies, proteins, recombinant proteins, peptides, small molecules and siRNA that target specific components of the complement pathway or complement activation per se. As a more detailed understanding of the host/pathogen interface and disease immunopathology is acquired, this will inform treatment options such as whether therapy should be by local or systemic administration or selective for a specific complement component (such as C5a), complement receptor, or whether complete inhibition of the entire complement system should be targeted (targeting C3). A trial of C5-specific antibody Eculizumab for severe COVID-19 has begun (SOLID-C19 NCT04288713). This is supported by preliminary data obtained using Eculizumab as an off-label treatment for four patients with severe COVID-19 in combination with anticoagulant therapy, anti-viral therapy, hydroxychloroquine, an antibiotic, vitamin C and non-invasive ventilation. All patients recovered and mean duration of the disease was 12.8 days (Diurno, Numis et al., 2020) . In addition, trials using a more targeted approach have been instigated using antibody blockade of the C5a fragment, while leaving the terminal effector (C5b-9) intact, which may be beneficial (BDB-001, China 2020L00003 (Gao et al., 2020), IFX-1 Europe NCT04333420). Indications that the coronavirus N protein binds MASP-2 and the detection of MASP-2 staining in post-mortem lung sections from COVID-19 patients (Gao et al., 2020 , Magro et al., 2020 , may support a trial of therapeutic anti-MASP-2 antibody (such as Narsoplimab (OMS721) to suppress lectin pathway activation. The sheer severity of the inflammatory response and cytokine storm justifies the use of therapeutic targeting of the meeting point of all three activation pathways, i.e. C3. This could potentially be achieved using a derivative of Compstatin, a cyclic peptide that binds C3 and prevents the action of C3 convertases (Mastaglio, Ruggeri et al., 2020) . Another This article is protected by copyright. All rights reserved option is the recombinant protein Mirococept (Smith & Smith, 2001) , which is a membrane-localising complement inhibitor based on a recombinant fragment of human Complement Receptor 1 (CR1; or CD35), attached to a membrane-binding peptide tail. The tail consists of a synthetic positively charged peptide that interacts with anionic phospholipids, joined to a membrane-inserting myristoyl tail (Pratt, Jones et al., 2003 , Smith & Smith, 2001 . It retains all biologic activity of native CR1 but is approximately a tenth of the size (24 kD) and binds cells to locally block complement activation, by inhibition of C3 and C5 convertases (Masaki, Matsumoto et al., 1992) . In principle, the local delivery of this potent therapeutic complement inhibitor could maximise localisation in the lung where the utmost inflammation occurs. Furthermore, the novel membraneinserting tail should enable local binding at high concentration (Smith, 2002) while avoiding unwanted side effects of systemic delivery. It should be noted that Mirococept is transferred in the circulation by erythrocytes also expressing native CR1, whose expression varies by up to 10-fold among healthy individuals (Herrera, Xiang et al., 1998) and, during the progressive phase of SARS, was reported to drop significantly (Wang, Chu et al., 2005) , possibly due to the release of small vesicles from the erythrocyte membrane leading to its proteolytic cleavage, as has been described previously in other viral infections (Pascual, Danielsson et al., 1994) . Restored levels of erythrocyte CR1 function in immune complex clearance could be an additional benefit of delivering a recombinant fragment of CR1 (Mirococept) to these patients. The causative agent of COVID-19 has an abundant display of glycoproteins on its outer surface and these could form potential ligands for several pattern recognition molecules (e.g. collectins) that are produced in the lungs along with other complement proteins, notably by type II alveolar cells and macrophages. The early findings in post-mortem lung tissue from COVID-19 patients are consistent with complement deposition triggered by the lectin complement pathway. Treatment with complement inhibitors against C3 or C5 or relevant activating pathways could potentially stem the downstream inflammatory This article is protected by copyright. All rights reserved response and capillary leak, assuming adequate tissue penetration of drug to the site of complement activation. This could reduce lung inflammation and secretion volume and deliver increased blood oxygenation and reduced need for respiratory support. It might also reduce the systemic complications of ARDS including MOF and coagulopathy mediated by the lectin pathway. There is urgency to test this hypothesis by clinical trial with Phase II or Phase III tested therapeutic agents. This article is protected by copyright. All rights reserved collectins (e.g. CL-11, collectin-11; and MBL, Mannose Binding Lectin) and ficolins for the lectin pathway. PRMs bind to pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Following this, cleavage of complement factors C4 and C2 generates C3 convertase (C4bC2b) which cleaves C3 to C3a and C3b. C3b binds factor B which is cleaved by factor D to generate C3bBb, the alternative pathway convertase which results in amplification of C3b from C3. The two C5 convertases (C4bC2bC3b and C3bBbC3b) cleave C5 into C5a and C5b, the latter alongside C6, C7, C8 and C9 forming the membrane attack complex (MAC) C5b-9. Meanwhile the other products of C3 cleavage (C3a and the end-metabolite of C3b called C3d) and C5 cleavage (C5a) have a number of roles including opsonisation, inflammation and the recruitment of the adaptive immune system. In the coagulation cascade prothrombin is converted to thrombin which in turn converts fibrinogen to fibrin and factor XIII to factor XIIIa. 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All rights reserved Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion Site-specific analysis of the SARS-CoV-2 glycan shield Structure of a C-type mannose-binding protein complexed with an oligosaccharide Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Factors associated with prolonged viral RNA shedding in patients with COVID-19 Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis pHdependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN Role of the coronavirus E viroporin protein transmembrane domain in virus assembly Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells Influence of FcgammaRIIA and MBL polymorphisms on severe acute respiratory syndrome Accepted Article This article is protected by copyright. All rights reserved Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19 Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection Chicken mannose binding lectin has antiviral activity towards infectious bronchitis virus The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha A pneumonia outbreak associated with a new coronavirus of probable bat origin A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms China Novel Coronavirus I, Research T (2020) A Novel Coronavirus from Patients with Pneumonia in China Accepted Article Previously published research by our laboratories was supported by the UK Medical stabilises this clot by cross-linking fibrin. Cross talk between the complement system and the coagulation system occurs through the actions of the MBL-associated serine proteases (MASPs). MASP-2 can convert prothrombin to thrombin while MASP-1 can act like thrombin and convert fibrinogen to fibrin. (Adapted from Nauser et al., 2018 , Shimogawa, Morioka et al., 2017 . For a more extensive review of complementcoagulation interactions, see (Lupu, Keshari et al., 2014) .