SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation. (2nd July 2021)

• Record Type: Journal Article
• Authors: Thorne, Lucy G; Reuschl, Ann‐Kathrin; Zuliani‐Alvarez, Lorena; Whelan, Matthew V X; Turner, Jane; Noursadeghi, Mahdad; Jolly, Clare; Towers, Greg J
• Is Part Of: EMBO journal. Volume 40:Number 15(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-02
• Subjects: epithelial -- inflammation -- macrophage -- RNA sensing -- SARS‐CoV‐2; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021107826
• Languages: English
• ISSNs: 0261-4189

Abstract

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. SYNOPSIS: SARS‐CoV‐2 induces a robust, delayed innate immune response in airway epithelial cells, driven by activation of RNA sensors, which propagates inflammation through macrophage activation. SARS‐CoV‐2 activates RNA sensors and consequent inflammatory responses in lung epithelial cells. Epithelial RNA sensing responses drive pro‐inflammatory macrophage activation. Exogenous inflammatory stimuli exacerbate responses to SARS‐CoV‐2 in both epithelial cells and macrophages. Immunomodulators inhibit RNA sensing responses and consequent macrophage inflammation. Abstract : SARS‐CoV‐2 induces a robust innate immune response via activation of RNA sensors in airway epithelial cells to propagate inflammation through macrophage activation.