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

Salvi, V.; Nguyen, H. O.; Sozio, F.; Schioppa, T.; Laffranchi, M.; Scapini, P.; Passari, M.; Barbazza, I.; Tiberio, L.; Tamassia, N.; Garlanda, C.; Del Prete, A.; Cassatella, M.; Mantovani, A.; Sozzani, S.; Bosisio, D.

doi:10.1101/2021.04.15.439839

bioRxiv · 10.1101/2021.04.15.439839

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

Salvi, V.·Nguyen, H. O.·Sozio, F.·Schioppa, T.·Laffranchi, M.·Scapini, P.·Passari, M.·Barbazza, I.·Tiberio, L.·Tamassia, N.·Garlanda, C.·Del Prete, A.·Cassatella, M.·Mantovani, A.·Sozzani, S.·Bosisio, D.

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Abstract

The inflammatory and IFN pathways of innate immunity play a key role in both 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 identify single-stranded RNA (ssRNA) fragments from 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 functions, 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 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 identify TLR7/8 as crucial cellular sensors of ssRNAs encoded by SARS-CoV-2 involved in host resistance and disease pathogenesis of COVID-19.

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Salvi, V., Nguyen, H. O., Sozio, F., Schioppa, T., Laffranchi, M., Scapini, P., Passari, M., Barbazza, I., Tiberio, L., Tamassia, N., Garlanda, C., Del Prete, A., Cassatella, M., Mantovani, A., Sozzani, S., Bosisio, D.. 2021-04-15. SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8. https://doi.org/10.1101/2021.04.15.439839

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