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SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation
Author(s) -
Thorne Lucy G,
Reuschl AnnKathrin,
ZulianiAlvarez Lorena,
Whelan Matthew V X,
Turner Jane,
Noursadeghi Mahdad,
Jolly Clare,
Towers Greg J
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2021107826
Subject(s) - inflammation , biology , mda5 , innate immune system , rig i , immune system , immunology , macrophage , cytokine , lung , rna , microbiology and biotechnology , rna interference , gene , medicine , in vitro , biochemistry
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.