TY - JOUR AU - Salvi, Valentina AU - Nguyen, Hoang Oanh AU - Sozio, Francesca AU - Schioppa, Tiziana AU - Gaudenzi, Carolina AU - Laffranchi, Mattia AU - Scapini, Patrizia AU - Passari, Mauro AU - Barbazza, Ilaria AU - Tiberio, Laura AU - Tamassia, Nicola AU - Garlanda, Cecilia AU - Del Prete, Annalisa AU - Cassatella, Marco A. AU - Mantovani, Alberto AU - Sozzani, Silvano AU - Bosisio, Daniela T1 - SARS-CoV-2–associated ssRNAs activate inflammation and immunity via TLR7/8 PY - 2021/09/22/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.150542 VL - 6 IS - 18 UR - https://doi.org/10.1172/jci.insight.150542 PB - The American Society for Clinical Investigation ER -