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.
Highlights
As of middle of August, 2021, COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than two hundred and seven million cases and more than four million deaths globally.Five to ten% of SARS-CoV-2 infected subjects progress, to severe or critical disease, requiring mechanical ventilation and admission to intensive care unit [1,2]
Moving from in vitro evidences on the protective role played by plasmacytoid dendritic cells-released type I IFN in the early phase of SARS-CoV-2 infection, here we characterized ex vivo the pDC phenotype and the balance between antiviral and pro-inflammatory cytokines of COVID-19 patients stratified according to disease severity
Our study confirms in COVID-19 the crucial and protective role of pDC/ type I IFN axis, whose deeper understanding may contribute to the development of novel pharmacological strategies and/or host-directed therapies aimed at boosting pDC response since the early phases of SARS-CoV-2 infection
Summary
As of middle of August, 2021, COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than two hundred and seven million cases and more than four million deaths globally (https://covid19.who.int/). Five to ten% of SARS-CoV-2 infected subjects progress, to severe or critical disease, requiring mechanical ventilation and admission to intensive care unit [1,2]. Severe pneumonia caused by SARS-CoV-2 is marked by immune system dysfunction and systemic hyperinflammation leading to acute respiratory distress syndrome, macrophage activation, hypercytokinemia and coagulopathy [4]. In the majority of the cases SARS-CoV-2 infection can be asymptomatic with a rate of presentation estimated to be at least around 17% of total cases [5]. Understanding the immunological features of these subjects is challenging but is of key importance to comprehend early events controlling SARS-CoV-2 replication
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