In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 9 ( 2021-9-2), p. e1009878-
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009878
DOI:
10.1371/journal.ppat.1009878.g001
DOI:
10.1371/journal.ppat.1009878.g002
DOI:
10.1371/journal.ppat.1009878.g003
DOI:
10.1371/journal.ppat.1009878.g004
DOI:
10.1371/journal.ppat.1009878.g005
DOI:
10.1371/journal.ppat.1009878.g006
DOI:
10.1371/journal.ppat.1009878.g007
DOI:
10.1371/journal.ppat.1009878.s001
DOI:
10.1371/journal.ppat.1009878.s002
DOI:
10.1371/journal.ppat.1009878.s003
DOI:
10.1371/journal.ppat.1009878.s004
DOI:
10.1371/journal.ppat.1009878.s005
DOI:
10.1371/journal.ppat.1009878.s006
DOI:
10.1371/journal.ppat.1009878.s007
DOI:
10.1371/journal.ppat.1009878.s008
DOI:
10.1371/journal.ppat.1009878.s009
DOI:
10.1371/journal.ppat.1009878.s010
DOI:
10.1371/journal.ppat.1009878.r001
DOI:
10.1371/journal.ppat.1009878.r002
DOI:
10.1371/journal.ppat.1009878.r003
DOI:
10.1371/journal.ppat.1009878.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
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