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

Bingyu Yan,Shahram Kordasti,Matthew R Olson,Konstantinos D Alysandratos,Jack Bibby,Daniel Chauss,Jason R Spence,Nathalie Niyonzima,Didier Portilla,Martin Kolev,Sonja Ghidelli-Disse,Arian Laurence,Behdad Afzali,Jonathan Z Sexton,Majid Kazemian,Claudia Kemper,Luopin Wang,Tilo Freiwald,Darrell N Kotton,Stefania Pittaluga,Christiane E Wobus,Carmen Mirabelli,Eva-Maria Nichols,Tristan Frum,Marcus Bantscheff,Michail S Lionakis ,Nazish T Malik ,Erin E West ,Charles J Zhang ,Richard I Gregory

doi:10.1126/sciimmunol.abg0833

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 (ACE) 2, 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.

Highlights

Coronavirus disease 2019 (COVID-19), a viral pneumonia caused by a beta coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic
We compared the transcriptomes of patients with controls using gene set enrichment analysis (GSEA) [14] and found 36 canonical pathways curated by the Molecular Signatures Database (MSigDB) to be induced in patients compared with controls (Fig. 1A and table S1B)
We examined the transcriptomes of primary normal human bronchial epithelial (NHBE) cells infected in vitro with SARS-CoV-2, which again identified several complement pathways as highly enriched in infected cells

Summary

Introduction

Coronavirus disease 2019 (COVID-19), a viral pneumonia caused by a beta coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic. Patients with COVID-19 present variable clinical symptoms, ranging from a mild upper respiratory tract illness to a severe disease with life-threatening complications, characterized by combinations of acute respiratory distress syndrome (ARDS); coagulopathy; vasculitis; and kidney, liver, and gastrointestinal injuries [1]. Survivors, and those with milder presentations, may suffer from loss of normal tissue function due to persistent inflammation and/or fibrosis [2, 3]. Complement factor B (CFB) is a key component of the alternative pathway C3 convertase. C3b generation triggers subsequent activation of C5 into C5a and C5b, with the latter seeding the formation of the lytic membrane attack

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