SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy

Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-kappa B phosphorylation (pNF-kappa B) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-kappa B and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-kappa B and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.

Automated summary

Cardiopulmonary complications caused by SARS-CoV-2 are major contributors to mortality. IL-18 has been identified as a novel mediator of cardiopulmonary pathologies, but its regulation through SARS-CoV-2 signaling is unknown. IL-18 was found to stratify mortality and hospitalization burden in COVID-19 patients. Spike protein exposure induced IL-18 expression and cardiac fibrosis in hACE2 mice. Spike protein inhibited mitophagy and increased reactive oxygen species, leading to NLRP3 inflammasome activation and IL-18 expression. Inhibition of IL-18 improved cardiac fibrosis and dysfunction. The reduced mitophagy-inflammasome link suggests IL-18 and mitophagy as potential therapeutic targets during COVID-19 pathogenesis.