Abstract SARS‐CoV‐2 infection causes broad‐spectrum immunopathological disease, exacerbated by inflammatory co‐morbidities. A better understanding of mechanisms underpinning virus‐associated inflammation is required to develop effective therapeutics. Here, we discover that SARS‐CoV‐2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through the activation of cytoplasmic RNA sensors RIG‐I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing or by inhibiting downstream signalling pathways. SARS‐CoV‐2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS‐CoV‐2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation‐associated COVID‐19. SARS‐CoV‐2 induces a robust innate immune response via activation of RNA sensors in airway epithelial cells to propagate inflammation through macrophage activation.
【저자키워드】 immunology, Inflammation, Macrophage, SARS‐CoV‐2, Microbiology, Virology & Host Pathogen Interaction, epithelial, RNA sensing, 【초록키워드】 Macrophage, innate immune response, macrophages, Infection, Local, cytokine, airway, COVID‐19, RNA, SARS‐CoV‐2, MDA5, epithelial cells, human macrophage, disease, mechanism, macrophage activation, cytokine production, Lung epithelial cells, Inflammatory mediators, Inflammatory, Pathways, inflammatory state, airway epithelial cells, epithelial cell, mediators, Activation, SARS‐CoV‐2 infection, lung epithelium, downstream, triggering, inflammatory stimuli, cellular activation, innate immune pathways, mitigate, effective, Cell, inflammatory mediator, robust, ENhance, produced, develop, required, exacerbated, replicate, cytoplasmic, induce, cause, inhibiting, stimulate, lung epithelial cell, immunopathological, exacerbate, airway epithelial cell, innate immune pathway, 【제목키워드】 Macrophage, Infection, SARS‐CoV‐2,