Tamassia, N. | bioRxiv Science

bioRxiv2021

Identification and characterization of human CD34+ and CD34dim/- neutrophil committed progenitors

We report the identification of human CD66b-CD64dimCD115- neutrophil-committed progenitors within SSClowCD45dimCD34+ and CD34dim/- bone marrow cells, that we named neutrophil myeloblast (NMs). CD34+ and CD34dim/-NMs resulted as either CD45RA+ or CD45RA-, with CD34+CD45RA-NMs found as selectively expanded in chronic-phase chronic myeloid leukemia patients. By scRNA-seq experiments, CD34+ and CD34dim/-NMs were found to consist of combinations of four cell clusters, characterized by different maturation stages and distributed along two differentiation routes. Cell clusters were identified by neutrophil-specific gene profiles, one of them associated to an interferon-stimulated gene (ISG) signature, hence supporting recently identified expansions of mature neutrophil subsets expressing ISGs in blood of diseased individuals. Altogether, our data shed light on the very early phases of neutrophil ontogeny.

immunology↗

bioRxiv2021

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

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.

immunology↗