Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection.

Abstract:

:Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality-effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.

journal_name

Nat Med

journal_title

Nature medicine

authors

Ramlall V,Thangaraj PM,Meydan C,Foox J,Butler D,Kim J,May B,De Freitas JK,Glicksberg BS,Mason CE,Tatonetti NP,Shapira SD

doi

10.1038/s41591-020-1021-2

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

1609-1615

issue

10

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-020-1021-2

journal_volume

26

pub_type

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