Interferon-Lambda Intranasal Protection and Differential Sex Pathology in a Murine Model of SARS-CoV-2 Infection

mBio. 2021 Dec 21;12(6):e0275621. doi: 10.1128/mBio.02756-21. Epub 2021 Nov 2.

Abstract

Outbreaks of emerging viral pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major medical challenge. There is a pressing need for antivirals that can be rapidly deployed to curb infection and dissemination. We determined the efficacy of interferon lambda-1 (IFN-λ) as a broad-spectrum antiviral agent to inhibit SARS-CoV-2 infection and reduce pathology in a mouse model of disease. IFN-λ significantly limited SARS-CoV-2 production in primary human bronchial epithelial cells in culture. Pretreatment of human lung cells with IFN-λ completely blocked infectious virus production, and treatment with IFN-λ at the time of infection inhibited virus production more than 10-fold. To interrogate the protective effects of IFN-λ in response to SARS-CoV-2 infection, transgenic mice expressing the human angiotensin-converting enzyme 2 (ACE-2) were tested. One dose of IFN-λ administered intranasally was found to reduce animal morbidity and mortality. Our study with SARS-CoV-2 also revealed a sex differential in disease outcome. Male mice had higher mortality, reflecting the more severe symptoms and mortality found in male patients infected with SARS-CoV-2. The results indicate that IFN-λ potentially can treat early stages of SARS-CoV-2 infection and decrease pathology, and this murine model can be used to investigate the sex differential documented in COVID-19. IMPORTANCE The COVID-19 pandemic has claimed millions of lives worldwide. In this report, we used a preclinical mouse model to investigate the prophylactic and therapeutic value of intranasal IFN-λ for this acute respiratory disease. Specific vaccines have been responsible for curbing the transmission of SARS-CoV-2 in developed nations. However, vaccines require time to generate and keep pace with antigenic variants. There is a need for broad-spectrum prophylactic and therapeutic agents to combat new emerging viral pathogens. Our mouse model suggests IFN-λ has clinical utility, and it reflects the well-documented finding that male COVID-19 patients manifest more severe symptoms and mortality. Understanding this sex bias is critical for considering therapeutic approaches to COVID-19.

Keywords: COVID-19; SARS-CoV-2; antiviral; interferon; lung infection; murine model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Bronchi / cytology
  • COVID-19 / immunology*
  • COVID-19 / therapy*
  • Disease Models, Animal
  • Epithelial Cells / drug effects*
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Female
  • HEK293 Cells
  • Humans
  • Interferons / classification
  • Interferons / immunology*
  • Interferons / pharmacology*
  • Lung / drug effects
  • Lung / pathology
  • Lung / virology
  • Male
  • Mice
  • Mice, Transgenic
  • Risk Factors
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / immunology*
  • Sex Factors

Substances

  • Antiviral Agents
  • Interferons
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2