The role of complement in COVID-19

National Heart, Lung, And Blood Institute

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Abstract

Our analysis of publically available scRNA-seq data from the lungs of patients with severe COVID-19 revealed that the expression induction of cell intrinsic complement is among the most highly induced pathways by SARS-CoV2 infection in lung epithelial and liver cells. Further, within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB. Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all 15 complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NFkB-signaling, such as anti-viral agents, may serve as an effective clinical strategy. This manuscript has been accepted by Science Immunology. In addition, we have now shown that dysregulation of the CD46-driven Th1 shut-down program (via changes in Vitamin D intermediates) contribute to Th1 hyperactivation in the lungs of patients with severe COVID.