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

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.

SARS-CoV-2 infection in a pediatrics STAT1 GOF patient under Ruxolitinib therapy-a matter of balance?

“…In summary, the maintenance of ruxolitinib treatment in this STAT1 GOF patient with SARS-CoV-2 infection was safe and resulted in a balanced residual type I interferon response sufficient to control viral infection whilst avoiding an uncontrolled inflammatory response. Recently, using human lung epithelial cell lines, ruxolitinib therapy was shown to normalize interferon signature genes, induced by SARS-CoV-2 infection, without affecting NF-κB-regulated genes, further supporting our observation [ 9 ]. In addition, case reports on its beneficial effect have been described in patients with myelofibrosis and rheumatoid diseases and a recent trial evaluating baricitinib and remdesivir in COVID-19 pneumonia showed promising results [ 10 – 12 ].…”

Complement dysregulation is associated with severe COVID-19 illness

“…32 CFB deposition was also observed in the lung tissue of COVID-19 patients, and a CFB inhibitor blocked the C3a generated by infection of respiratory epithelial cells with SARS-CoV-2. 33,34 Pekayvaz et al 35 further showed upregulation of complement factor D (CFD), produced mainly in adipocytes, in monocytes of severe COVID-19 patients. Ma et al 36 demonstrated that enhanced activation of the APC is associated with markers of endothelial injury and hypercoagulability in severe COVID-19 patients as compared to other non-COVID-19 patients admitted to the intensive care unit with acute respiratory failure.…”

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

“…Several studies are now emerging implicating complement or its regulation in COVID-19. In one study, patients with severe COVID-19 were found to have increased levels of Factor B and Ba, a zymogen which downregulates complement inhibitory protein expression 46 . In another, C3 expression was found to correlate with viral load, with an increase in its expression in AT2 cells from lung biopsy and BAL scRNAseq datasets, and its processing into its active form in SARS-CoV-2 infected lung epithelial cell lines in vitro 47 .…”