Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

Hurler, Lisa; Szilágyi, Ágnes; Mescia, Federica; Bergamaschi, Laura; Mező, Blanka; Sinkovits, György; Réti, Marienn; Müller, Veronika; Iványi, Zsolt; Gál, János; Gopcsa, László; Reményi, Péter; Szathmáry, Beáta; Lakatos, Botond; Szlávik, János; Bobek, Ilona; Prohászka, Zita Z.; Förhécz, Zsolt; Csuka, Dorottya; Kajdácsi, Erika; Cervenak, László; Kiszel, Petra; Masszi, Tamás; Vályi‐Nagy, István; Würzner, Reinhard; Lyons, Paul; Toonen, Erik J. M.; Prohászka, Zoltán

doi:10.3389/fimmu.2023.1162171

Cited by 14 publications

(13 citation statements)

References 70 publications

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“…SARS-CoV-2 itself can activate the complement system directly through the lectin pathway (Ali et al, 2021 ; Gao et al, 2022 ; Hurler et al, 2023 ; Magro et al, 2020 ; Malaquias et al, 2021 ) and the alternative pathway (Yu et al, 2020 ). Specifically, SARS-CoV-2 Spike and nucleocapsid proteins are directly recognized by the lectin pathway components, leading to complement activation and the subsequent complement deposition (C3b) on virions (Ali et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Bermejo-Jambrina,

van der Donk,

van Hamme

et al. 2024

EMBO J

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Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here, we uncover the role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Bermejo-Jambrina,

van der Donk,

van Hamme

et al. 2024

EMBO J

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“…It has been found to play a significant role in the hyper-inflammation and thrombotic microangiopathy observed in severe CoVID-19 cases (66). SARS-CoV-2 has the ability to trigger the activation of all three pathways of the complement system: the classical, alternative, and lectin pathways (70)(71)(72). Furthermore, SARS-CoV-2 was also found to promote the synthesis and release of complement factors from infected respiratory epithelial and endothelial cells through Janus kinase 1 (JAK1)-dependent and/or JAK2-dependent pathways, interestingly parallel to the release of procoagulant (clot-promoting) factors (73,74).…”

Section: Factor H Regulates Classical Complement Pathway Activation A...mentioning

confidence: 99%

Activation of Complement by Human Fibrin Clots: involvement of C1q and factor H

Kang,

Varghese,

Pondman

et al. 2023

Preprint

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The classical pathway of the complement system is activated by the binding of C1q in the C1 complex to the target activator including immune complexes. Factor H is regarded as the key downregulatory protein of the alternative pathway of complement. However, C1q and factor H both bind to target surfaces via charge distribution patterns. For few targets, C1q and factor H compete for binding to common or overlapping sites. Factor H, therefore, can effectively regulate the classical pathway activation by such targets, in addition to its previously characterized role in the alternative pathway. Both C1q and factor H are reported to recognize foreign or altered-self materials. Clots, formed by the coagulation system, are an example of altered self. Factor H is present abundantly in platelets and is a well-known substrate for FXIIIa. Here, we investigated whether clots activate the classical pathway of complement and whether this is regulated by factor H. We show here that both C1q and factor H bind to fibrin formed in microtitre plates as well as fibrin clots formed under in vitro physiological conditions. Both C1q and factor H become covalently bound to fibrin clots and this is mediated via FXIIIa. We also show that fibrin clots activate the classical pathway of complement, as demonstrated by C4 consumption and membrane attack complex detection assays. Thus, factor H downregulates the classical pathway activation induced by fibrin clots. These results elucidate the intricate molecular mechanisms through which the complement and coagulation pathways intersect and have regulatory consequences.

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“…The lectin pathway is clearly implicated in the pathogenesis of severe COVID-19. The concentration of lectin pathway-specific products, such as the MASP-1/C1-INH complex, have been correlated with COVID-19 severity [ 89 ]. Binding assays have shown that the SARS-CoV-2 N protein can interact with MASP-2, and complement deposition assays have linked N protein levels to activated C3 in a calcium-dependent manner [ 90 ] (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This may be because MBL can suppress TNF-α and IFN-γ in natural killer cells and attenuate the acute immune response. Other MBL polymorphisms showed no correlation with any disease outcomes [ 89 , 93 ]. Once again, the complement system’s activation-independent functions seem to play an adaptive role, as opposed to downstream complement activation effects.…”

Section: Introductionmentioning

confidence: 99%

Emerging role of complement in COVID-19 and other respiratory virus diseases

Xiao,

Ellsworth,

Qin

2024

Cell. Mol. Life Sci.

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The complement system, a key component of innate immunity, provides the first line of defense against bacterial infection; however, the COVID-19 pandemic has revealed that it may also engender severe complications in the context of viral respiratory disease. Here, we review the mechanisms of complement activation and regulation and explore their roles in both protecting against infection and exacerbating disease. We discuss emerging evidence related to complement-targeted therapeutics in COVID-19 and compare the role of the complement in other respiratory viral diseases like influenza and respiratory syncytial virus. We review recent mechanistic studies and animal models that can be used for further investigation. Novel knockout studies are proposed to better understand the nuances of the activation of the complement system in respiratory viral diseases.

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Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

Cited by 14 publications

References 70 publications

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Activation of Complement by Human Fibrin Clots: involvement of C1q and factor H

Emerging role of complement in COVID-19 and other respiratory virus diseases

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