The state of complement in COVID-19

Afzali, Behdad; Noris, Marina; Lambrecht, Bart; Kemper, Claudia

doi:10.1038/s41577-021-00665-1

Cited by 211 publications

(228 citation statements)

References 149 publications

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“…Further proof-of-concept that C5a has thrombogenic effects on endothelial cells comes from data showing that C5a inhibition halts the platelet aggregation induced by sera from severe COVID-19 patients, possibly through the exocytosis of vWF and P-selectin ( 48 ). Finally, data from the UK show that genetic predisposition to complement dysregulation is a risk factors for morbidity and death from SARS-CoV-2 infection, which indicates that hyperactivation of complement is a hallmark feature of the pathophysiology of severe COVID-19 ( 86 , 87 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation

et al. 2022

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Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA. In vitro experiments were performed on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). The expression of adhesive molecules was studied by immunofluorescence and leukocyte adhesion and platelet aggregation were assessed under flow conditions. Angiotensin converting enzyme 2 (ACE2) and AMPK expression were investigated by Western Blot analysis. In addition, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist, or complement inhibitors. Our results show that significant levels of spike protein were found in the 30.4% of severe COVID-19 patients. In vitro, the activation of endothelial cells with S1 protein, via ACE2, impaired AMPK signalling, leading to robust leukocyte recruitment due to increased adhesive molecule expression and thrombomodulin loss. This S1-induced pro-inflammatory phenotype led to exuberant C3 and C5b-9 deposition on endothelial cells, along with C3a and C5a generation that further amplified S1-induced complement activation. Functional blockade of ACE2 or complement inhibition halted S1-induced platelet aggregates by limiting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. Overall, we demonstrate that SARS-CoV-2-derived S1 is sufficient in itself to propagate inflammatory and thrombogenic processes in the microvasculature, amplified by the complement system, recapitulating the thromboembolic complications of COVID-19.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation

et al. 2022

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“…C3, C5 and their receptors have also been implicated in pathogenesis of asthma, cystic fibrosis, and idiopathic pulmonary fibrosis 16 , 55 . In COVID-19, excessive activation of C3 and C5a have been linked to increased viral loads, coagulation, and lung injury 20 , 57 .…”

Section: Discussionmentioning

confidence: 99%

A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins

Chaudhary

Jayaraman²,

Reinhardt³

et al. 2022

Mucosal Immunology

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To understand functional duality of the complement system in host defense and lung injury, a more comprehensive view of its localized production in the lung, and the impact of age on complement production are essential. Here, we explored the expression of complement genes through computational analysis of preexisting single cell RNA sequencing data from lung transcriptomes of healthy young (3 months) and old C57BL/6 mice (24 months), and humans. We characterized the distribution of 48 complement genes. Across 28 distinct immune and non-immune cell types in mice, mesothelial cells expressed the greatest number of complement genes (e.g., C1ra , C2, C3 ), and regulators (e.g., Serping1 , Cfh ). C5 was abundant in type II alveolar epithelial cells and C1q in interstitial lung macrophages. There were only moderate differences in gene expression between young and old mice. Among 57 human lung cell types, mesothelial cells showed abundant complement expression. A few differences in gene expression (e.g., FCN1 , CFI , C6 , C7 ) were also evident between mice and human lung cells. Our findings present a novel perspective on the expression patterns of complement genes in normal lungs. These findings highlight the potential functions of complement in tissue-specific homeostasis and immunity and may foster a mechanistic understanding of its role in lung health and disease.

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“…Other antibodies could have bound to the receptors on the surfaces of the phagocytic cells, triggering the phagocytosis on the infected cells. Finally, antibodies activating the complement system, opsonizing and promoting the phagocytosis of infected cells, have been shown to play a role in viral clearance [ 21 , 22 ]. Therefore, we believe that a dual vaccination, based on an Omicron vaccine in addition to the current mRNA vaccine, could help to protect against SARS-CoV-2 variants, although some different amino acids are present in the spike sequence.…”

Section: Discussionmentioning

confidence: 99%

Omicron Infection Evokes Cross-Protection against SARS-CoV-2 Variants in Vaccinees

et al. 2022

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Due to the rapid global spread of the Omicron (B.1.1.529) variant, efforts to scale up COVID-19 booster vaccination have been improved, especially in light of the increasing evidence of reduced neutralizing antibody (NT Ab) over time in vaccinated subjects. In this study, neutralizing antibody responses against the Wild-Type, Delta, and Omicron strains were evaluated among vaccinees, both infected with Omicron or uninfected, and non-vaccinated subjects infected with Omicron. The aim of the study was to compare the cross-protective humoral response to the variant strains induced by vaccination and/or Omicron infection. The results showed a significant difference in the neutralizing antibody response between the vaccinees and the Omicron-infected vaccinated subjects against the three tested strains (p < 0.001), confirming the booster effect of the Omicron infection in the vaccinees. By contrast, Omicron infection only did not enhance the antibody response to the other variants, indicating a lack of cross-protection. These results suggest the importance of updating the current formulation of the SARS-CoV-2 vaccine to protect people against the Omicron subvariants. A specific Omicron vaccine, administered as a booster for the previously adopted mRNA vaccines, may protect against a wider range of SARS-CoV-2 variants. However, it is unlikely that the Omicron vaccine alone would be able to protect non-vaccinated subjects against other circulating variants.

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The state of complement in COVID-19

Cited by 211 publications

References 149 publications

SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation

SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation

A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins

Omicron Infection Evokes Cross-Protection against SARS-CoV-2 Variants in Vaccinees

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