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bioRxiv · 10.1101/2020.12.23.424169

SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation

Thorne, L. G.·Reuschl, A.-K.·Zuliani-Alvarez, L.·Whelan, M. V. X.·Noursadeghi, M.·Jolly, C.·Towers, G. J.
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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 activation of cytoplasmic RNA-ensors 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. HighlightsO_LISARS-CoV-2 activates RNA sensors and consequent inflammatory responses in lung epithelial cells C_LIO_LIEpithelial RNA sensing responses drive pro-inflammatory macrophage activation C_LIO_LIExogenous inflammatory stimuli exacerbate responses to SARS-CoV-2 in both eplithelial cells and macrophages C_LIO_LIImmunomodulators inhibit RNA sensing responses and consequent macrophage inflammation C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/424169v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@b07adborg.highwire.dtl.DTLVardef@51ddf7org.highwire.dtl.DTLVardef@c38f9aorg.highwire.dtl.DTLVardef@108db57_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Thorne, L. G., Reuschl, A.-K., Zuliani-Alvarez, L., Whelan, M. V. X., Noursadeghi, M., Jolly, C., Towers, G. J.. 2020-12-23. SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation. https://doi.org/10.1101/2020.12.23.424169

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