SARS-CoV-2 Z-RNA activates the ZBP1-RIPK3 pathway to promote virus-induced inflammatory responses

Abstract

SARS-CoV-2 infection can trigger strong inflammatory responses and cause severe lung damage in COVID-19 patients with critical illness. However, the molecular mechanisms by which the infection induces excessive inflammatory responses are not fully understood. Here, we report that SARS-CoV-2 infection results in the formation of viral Z-RNA in the cytoplasm of infected cells and thereby activates the ZBP1-RIPK3 pathway. Pharmacological inhibition of RIPK3 by GSK872 or genetic deletion of MLKL reduced SARS-CoV-2-induced IL-1β release. ZBP1 or RIPK3 deficiency leads to reduced production of both inflammatory cytokines and chemokines during SARS-CoV-2 infection both in vitro and in vivo. Furthermore, deletion of ZBP1 or RIPK3 alleviated SARS-CoV-2 infection-induced immune cell infiltration and lung damage in infected mouse models. These results suggest that the ZBP1-RIPK3 pathway plays a critical role in SARS-CoV-2-induced inflammatory responses and lung damage. Our study provides novel insights into how SARS-CoV-2 infection triggers inflammatory responses and lung pathology, and implicates the therapeutic potential of targeting ZBP1-RIPK3 axis in treating COVID-19.

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

“…Necroptosis occurs via the RIPK3dependent activation of mixed lineage kinase domain like protein (MLKL), which forms oligomeric pore complexes that induce cellular lysis (15). However, many recent studies have identified complex roles for RIPK3 signaling in the coordination of inflammation, including the regulation of inflammatory transcriptional responses that occur independently of necroptosis (16)(17)(18)(19)(20)(21)(22)(23)(24). We and others have demonstrated that RIPK3 signaling in neurons is of particular importance for the control of neurotropic viral infections, as neuronal RIPK3 promotes a robust antimicrobial transcriptional program, including many interferon stimulated genes (ISGs), that restricts viral infection without inducing neuronal necroptosis (16,17).…”

ZBP1 inflames the SARS-CoV-2-infected lung

“…In severe influenza, ZBP1-initiated necroptosis and likely cell death-independent inflammatory gene expression, provoke lung inflammation. 8 Here, Li et al 3 extend these observations to COVID-19 by implicating ZBP1 in SARS-CoV-2-initiated lung damage. The authors first observed that in the human lung epithelium-derived cell line Calu-3, SARS-CoV-2 infection caused up-regulation of ZBP1 expression and triggered cell death, including necroptosis.…”

“…In a recent study of Cell Research , Li et al 3 provide new insights into how SARS-CoV-2 activates pathways of programmed cell death and consequent necro-inflammation, and how these pathways may contribute to the rampant lung inflammation seen in severe cases of COVID-19. Previously, the same group had reported that lung sections from fatal cases of COVID-19 manifested signs of both apoptosis and necroptosis, accompanied by a massive influx of inflammatory cells, necrotic cell debris, and fibrotic lung damage.…”

ZBP1-mediated macrophage necroptosis inhibits ASFV replication

“…Virus infection-induced ZBP1 activation needs ZBP1 to sense the virus-derived Z-RNA (30,44,45). Differently, Z-DNA sequences were predicted to be present in the ASFV genome using the Z-HUNT3 program (Fig.…”

“…Influenza A virus (IAV) replication generates Z-RNA in the nucleus so that ZBP1 initiates necroptosis activation in the nucleus and results in nuclear envelope disruption leakage of DNA into the cytosol (30). However, ZBP1 recognized viral Z-RNA and activated necroptosis in the vaccinia virus (VACV) cytoplasm or SARS-CoV-2 infected cells (44,45). Past studies have confirmed that early replication of ASFV occurs in the nucleus and subsequently replicates in the perinuclear viral factory (46,47).…”