JCI Insight (Sep 2021)

SARS-CoV-2–associated ssRNAs activate inflammation and immunity via TLR7/8

  • Valentina Salvi,
  • Hoang Oanh Nguyen,
  • Francesca Sozio,
  • Tiziana Schioppa,
  • Carolina Gaudenzi,
  • Mattia Laffranchi,
  • Patrizia Scapini,
  • Mauro Passari,
  • Ilaria Barbazza,
  • Laura Tiberio,
  • Nicola Tamassia,
  • Cecilia Garlanda,
  • Annalisa Del Prete,
  • Marco A. Cassatella,
  • Alberto Mantovani,
  • Silvano Sozzani,
  • Daniela Bosisio

Journal volume & issue
Vol. 6, no. 18

Abstract

Read online

The inflammatory and IFN pathways of innate immunity play a key role in the resistance and pathogenesis of coronavirus disease 2019 (COVID-19). Innate sensors and SARS-CoV-2–associated molecular patterns (SAMPs) remain to be completely defined. Here, we identified single-stranded RNA (ssRNA) fragments from the SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and function, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream of these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identified TLR7/8 as a crucial cellular sensor of ssRNAs encoded by SARS-CoV-2 involved in host resistance and the disease pathogenesis of COVID-19.

Keywords