Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection |
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| Authors: | Martina Severa Roberta A. Diotti Marilena P. Etna Fabiana Rizzo Stefano Fiore Daniela Ricci Marco Iannetta Alessandro Sinigaglia Alessandra Lodi Nicasio Mancini Elena Criscuolo Massimo Clementi Massimo Andreoni Stefano Balducci Luisa Barzon Paola Stefanelli Nicola Clementi Eliana M. Coccia |
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| Affiliation: | 1. Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy ; 2. Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy ; 3. Infectious Disease Clinic, Policlinico Tor Vergata, Rome, Italy ; 4. Department of Molecular Medicine, University of Padova, Padua, Italy ; 5. Metabolic Fitness Association, Monterotondo, Rome, Italy ; Washington University School of Medicine, UNITED STATES |
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| Abstract: | SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients. |
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