Dataset Information

Intranasal inoculation of IFN-λ resolves SARS-CoV-2 lung infection via the rapid reduction of viral burden and improvement of tissue damage.

ABSTRACT:

Introduction

The innate immune responses of upper airway could further our understanding toward antiviral strategies against SARS-CoV-2. We characterize the potential of interferon (IFN)-λ as an innate immune inducer for the rapid clearance of SARS-CoV-2 in the lung and the therapeutic efficacy of intranasal inoculation of IFN-λ to resolve acute lung infection.

Methods

Syrian golden hamsters were infected with SARS-CoV-2 and the dynamics of SARS-CoV-2 infection depending on IFN-λ inoculation were tested.

Results

SARS-CoV-2-infected Syrian golden hamsters exhibited a significant decrease in body weight and high viral mRNA level at 3 days post-infection (dpi). Although viral replication was reduced completely from 7 dpi, the pathologic findings remained prominent until 14 dpi in the lung of hamsters. The transcription of IFN-λ was significantly induced in response to SARS-CoV-2 infection with the increase of IFN-stimulated genes. Intranasal inoculation of IFN-λ restricted SARS-CoV-2 replication in the lungs of infected completely from 3 dpi with markedly reduction of inflammatory cytokines. The transcriptional phenotypes were altered to the direction of damage repair and tissue remodeling in the lungs of SARS-CoV-2-infected hamsters following intranasal inoculation of IFN-λ, which improved SARS-CoV-2-caused lung damage.

Conclusion

Collectively, our findings suggest that IFN-λ might be a potent innate immune inducer in the lung and intranasal inoculation of IFN-λ resolves SARS-CoV-2 infection with rapid viral clearance and improvement of lung damage.

SUBMITTER: Shin H

PROVIDER: S-EPMC9744928 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Intranasal inoculation of IFN-λ resolves SARS-CoV-2 lung infection via the rapid reduction of viral burden and improvement of tissue damage.

Shin Haeun H Kim Sujin S Jo Ara A Won Jina J Gil Chan Hee CH Yoon So Yeon SY Cha Hyunkyung H Kim Hyun Jik HJ

Frontiers in immunology 20221129

<h4>Introduction</h4>The innate immune responses of upper airway could further our understanding toward antiviral strategies against SARS-CoV-2. We characterize the potential of interferon (IFN)-λ as an innate immune inducer for the rapid clearance of SARS-CoV-2 in the lung and the therapeutic efficacy of intranasal inoculation of IFN-λ to resolve acute lung infection.<h4>Methods</h4>Syrian golden hamsters were infected with SARS-CoV-2 and the dynamics of SARS-CoV-2 infection depending on IFN-λ ...[more]

PMID: 36524125

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Project description:Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, the exact mechanisms of anti-flu activity of PLSCR1 in relation to its expression compartment and enzymatic activity, and the molecular and cellular mechanisms involved have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. We hypothesize that PLSCR1 protects hosts against IAV infection by regulating type 3 interferon (IFN-λ) signaling pathways. Our results showed that Plscr1 expression was highly induced by IAV infection in vivo and in epithelial cells treated with IFN-λ. We found that Plscr1 knockout (KO) mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for type 3 interferon receptor (Ifn-λr1) expression, and impaired expression of Ifn-λr1 and downstream ISGs may be responsible for delayed viral clearance in Plscr1 KO mice. In addition, Plscr1 interacted with Ifn-λr1 within the epithelial compartment following IAV infection, suggesting Plscr1 may modulate IFN-λ signaling via protein-protein interactions. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1 floxStop Foxj1-Cre + mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility, less inflammation and enhanced Ifn-λr1 expression in IAV infection. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

Dataset Information

Intranasal inoculation of IFN-λ resolves SARS-CoV-2 lung infection via the rapid reduction of viral burden and improvement of tissue damage.

Introduction

Methods

Results

Conclusion

Publications

Intranasal inoculation of IFN-λ resolves SARS-CoV-2 lung infection via the rapid reduction of viral burden and improvement of tissue damage.

Similar Datasets

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