Journal Article

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

Helminiak, Luke, Kirillov, Varvara, Mishra, Smruti, Sohn, Sook-Young, Hearing, Janet, Mackow, Erich, Hearing, Patrick, Mugavero, JoAnn, Gorbunova, Elena, Reich, Nancy C., Kim, Hwan Keun

2021

Overview

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. 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.

• Publisher: American Society for Microbiology
• Subject: ACE2 / Administration, Intranasal / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Animal models / Animals / Antigenic variation / antiviral / Antiviral agents / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Bronchi - cytology / Cell culture / Coronaviruses / COVID-19 / COVID-19 - immunology / COVID-19 - therapy / COVID-19 vaccines / Disease Models, Animal / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - immunology / Epithelial Cells - virology / Female / Females / HEK293 Cells / Host-Microbial Interactions / Humans / Immunity (Disease) / Inflammation / Interferon / Interferons - classification / Interferons - immunology / Interferons - pharmacology / Lung - drug effects / Lung - pathology / Lung - virology / lung infection / Male / Mice / Mice, Transgenic / Morbidity / Mortality / murine model / Pandemics / Pathogens / Pathology / Patients / Peptidyl-dipeptidase A / Phosphorylation / Research Article / Respiratory diseases / Risk Factors / SARS-CoV-2 / SARS-CoV-2 - drug effects / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / Sex / Sex Factors / Transgenic animals / Transgenic mice / Vaccines / Viral infections / Viruses