Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

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.

Transcriptional Profiling and Machine Learning Unveil a Concordant Biosignature of Type I Interferon-Inducible Host Response Across Nasal Swab and Pulmonary Tissue for COVID-19 Diagnosis

“…4) Interferon is one of the regulators of ACE2 receptor ( 22 ). Additionally, host IFN-I possesses high sensitivity to both SARS-CoV-2 virus and ACE2 receptors, especially in COVID-19 patients with asymptomatic manifestation ( 23 ), suggesting that understanding the genetic signature of IFN-I-associated genes in SARS-CoV-2 infection may serve as indicators of COVID-19 diagnosis. 5) Recent reports suggested that detection of IFN-I gene expression may be of great significance to measure the severity of COVID-19 ( 21 ), indicating that varied IFN-I-related gene profile may stratify the severity of COVID-19.…”

An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

“…Several studies have shown that the TLR7 response is critical for favorable outcome of COVID-19 [56,57], highlighting the clinical importance of the innate immune system in SARS-CoV-2 infection. However, in an in vitro study, it has been shown that SARS-CoV-2 induces a TLR7/8-dependent type I and III IFN response in peripheral blood mononuclear cells, which could be protective or may contribute to the cytokine storm observed in COVID-19 [58] and requires future investigation. Although there is a need for further investigation in this regard, IFN-α2b treatment has been shown to reduce viral replication, as well as IL-6 and CRP levels [59].…”

Pathogenesis of Respiratory Viral and Fungal Coinfections

“…During influenza infection, pDCs are a major source of type I IFNs, causing the expansion of antigen-specific T cells ( 415 – 418 ). pDC-derived type I IFNs also inhibit viral replication in airway epithelial cells following SARS-CoV-2 infection ( 419 – 421 ). They play a nonredundant role in host defense against Aspergillus infection.…”

“…More recently, it was shown that recruitment of pDCs into the lungs activates neutrophil NADPH activity to promote clearance of inhaled conidia ( 316 ). Importantly, severe COVID-19 patients show gene expression signatures of apoptosis in pDCs that correlate with reduced pDC frequency ( 278 , 405 , 419 , 421 ). Dysregulation of pDCs might contribute to depressed IFN signatures affecting susceptibility to fungal coinfections.…”