The state of complement in COVID-19.

Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.

Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

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

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.

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation.

Patients with coronavirus disease 2019 (COVID-19) present with a range of devastating acute clinical manifestations affecting the lungs, liver, kidneys and gut. The best-characterized entry receptor for the disease-causing virus SARS-CoV2, angiotensin converting enzyme (ACE) 2, is highly expressed in these tissues. However, the pathways that underlie the disease are still poorly understood. Here we show that the complement system is unexpectedly one of the intracellular pathways most highly induced by SARS-CoV2 infection in lung epithelial and liver cells. 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 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 NF-kB-signaling, such as anti-viral agents, may serve as an effective clinical strategy.

COVID-19: Complement, Coagulation, and Collateral Damage.

Coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory infection that is caused by the severe acute respiratory syndrome coronavirus 2. Although most people are immunocompetent to the virus, a small group fail to mount an effective antiviral response and develop chronic infections that trigger hyperinflammation. This results in major complications, including acute respiratory distress syndrome, disseminated intravascular coagulation, and multiorgan failure, which all carry poor prognoses. Emerging evidence suggests that the complement system plays a key role in this inflammatory reaction. Indeed, patients with severe COVID-19 show prominent complement activation in their lung, skin, and sera, and those individuals who were treated with complement inhibitors all recovered with no adverse reactions. These and other studies hint at complement's therapeutic potential in these sequalae, and thus, to support drug development, in this review, we provide a summary of COVID-19 and review complement's role in COVID-19 acute respiratory distress syndrome and coagulopathy.