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However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that GU-rich RNA sequences from the SARS-CoV-2 genome (i.e., SCV2-RNA1 and SCV2-RNA2) activate dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNAs, neutrophils were treated with either SCV2-RNAs or, as a control, R848 (a TLR7\/8 ligand), and were then analyzed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNAs in terms of TNF\u03b1, IL-1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression, and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similar to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease.<\/jats:p>","DOI":"10.3390\/cells11233785","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T04:56:25Z","timestamp":1669611385000},"page":"3785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["SARS-CoV-2-Associated ssRNAs Activate Human Neutrophils in a TLR8-Dependent Fashion"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5431-9610","authenticated-orcid":false,"given":"Elisa","family":"Gardiman","sequence":"first","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3910-4715","authenticated-orcid":false,"given":"Francisco","family":"Bianchetto-Aguilera","sequence":"additional","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gasperini","sequence":"additional","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0482-9898","authenticated-orcid":false,"given":"Laura","family":"Tiberio","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Scandola","sequence":"additional","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5746-3810","authenticated-orcid":false,"given":"Virginia","family":"Lotti","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Gibellini","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Salvi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-5365","authenticated-orcid":false,"given":"Daniela","family":"Bosisio","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco A.","family":"Cassatella","sequence":"additional","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2990-3003","authenticated-orcid":false,"given":"Nicola","family":"Tamassia","sequence":"additional","affiliation":[{"name":"General Pathology Section, Department of Medicine, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An interactive web-based dashboard to track COVID-19 in real time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. 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