Research ArticleCORONAVIRUS

SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation

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Science Immunology  07 Apr 2021:
Vol. 6, Issue 58, eabg0833
DOI: 10.1126/sciimmunol.abg0833

COVID-19 hyperactivates complement

The complement system is a series of innate immune system proteins that help antibodies and phagocytes identify and eliminate pathogens. Activation of the complement system correlates with COVID-19 severity, but the cells that produce complement and potential treatments to inhibit complement activation during SARS-CoV-2 infection are not known. Here, Yan et al. used transcriptomics from patient bronchoalveolar lavage and infection models to demonstrate that SARS-CoV-2 infection induced complement-related genes and the activated complement component C3a in respiratory epithelial cells. C3a production was tied to IFN-induced JAK1/2-STAT1 signaling. Inhibition of JAK1/2 with ruxolitinib, with or without an antiviral, or a cell-permeable complement inhibitor repressed C3a production in SARS-CoV-2–infected epithelial cells. Thus, the use of JAK1/2 inhibitors may inhibit pathologies in patients with severe COVID-19.

Abstract

Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys, and gut. Angiotensin-converting enzyme 2 (ACE2), the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid, and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-κB as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines but did not affect NF-κB–regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-κB signaling could potentially have clinical application for severe COVID-19.

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