Experimental and natural evidence of SARS-CoV-2 infection-induced activation of type I interferon responses
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ABSTRACT:
PROVIDER: PRJNA636173 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR11884700_1.fastq.gz | Fastqsanger.gz | |||
| SRR11884700_2.fastq.gz | Fastqsanger.gz | |||
| SRR11884701_1.fastq.gz | Fastqsanger.gz | |||
| SRR11884701_2.fastq.gz | Fastqsanger.gz | |||
| SRR11884702_1.fastq.gz | Fastqsanger.gz |
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Project description:Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells.
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated Interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN- production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Senescent Huh7 cells in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection and SARS-CoV-2 effectively inhibited IFIT1 in these cells. Proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Characterization of the role of different interferon stimulated genes on the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.
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Project description:Optimization of protective immune responses against SARS-CoV-2 remains an urgent worldwide priority. In this regard, type III interferon (Interferon-lambda, IFNl) restricts SARS-CoV-2 infection in vitro and treatment with IFNl limits infection, inflammation, and pathogenesis in murine models. Further, IFNl has been developed for clinical use to prevent illness during COVID-19. However, whether endogenous IFNl signaling has an impact on SARS-CoV-2 antiviral immunity and long-term immune protection in vivo is unknown. In this study, we identified a requirement for IFNl signaling in promoting viral clearance and protective immune programming in SARS-CoV-2 infection of mice. Both IFN and IFN-stimulated gene (ISG) expression in the lungs was independent of IFNl signaling. Instead, IFNl promoted generation of protective CD8 T cell responses against SARS-CoV-2 by facilitating accumulation of CD103+ DC in lung-draining lymph nodes. Conversely, CD8 T cell immunity to SARS-CoV-2 is independent of type I IFN signaling, revealing a unique dependence on IFNl. Overall, these studies demonstrate that IFNl is critical for protective innate and adaptive immunity upon infection with SARS-CoV-2, and suggest that IFNl serves as an immune adjuvant to support CD8 T cell immunity.
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