Neutrophil Elastase Regulates both Innate and Adaptive Immunity in SARS-CoV-2-Infected Mice 2260457

Abstract Introduction Neutrophil elastase (NE), encoded by ELANE, is a serine protease that contributes to both antimicrobial defense and inflammatory tissue injury. Our group has shown that pharmacologic inhibition of NE modulates immune responses and enhances vaccine efficacy. To define the role played by ELANE in antiviral immunity and disease severity, we examined the outcome of SARS-CoV-2 infection in wild-type (WT) C57BL/6J mice, ELANE knockout (ELANE) mice, and mice nasally treated with pharmacological inhibitors of NE. Methods Male and female mice were intranasally infected with the mouse-adapted SARS-CoV-2 MA10 and body weight and temperature were monitored to assess the severity of disease. Early host response to infection was determined by flow cytometry analysis of peripheral blood leukocyte subsets, viral load in lung tissues, and the profile of host mRNA responses. We also quantified anti-SARS-CoV-2 antibody responses in the bloodstream and mucosal tissues to determine the potential level of protection achieved against future infection. Results Both WT and ELANE mice exhibited transient hypothermia following infection with the mouse-adapted SARS-CoV-2 MA10. However, unlike WT mice, those lacking ELANE were protected from weight loss post-infection. Male and female ELANE mice displayed distinct immune signatures in the blood, with males presenting early in non-classical monocytes, as well as enhanced frequencies of B and T cells compared to WT controls. ELANE mice showed higher spike-specific IgG1 and IgG2c antibodies compared to WT controls. Additionally, in vitro, pharmacological NE inhibition with Alvelestat reduced viral plaque formation in a dose-dependent manner. Conclusion These findings identify NE as a critical regulator of host immunity and viral replication during SARS-CoV-2 infection. Ongoing single-cell RNA sequencing of infected lungs will further define NE-dependent programs governing the protective versus pathogenic immunity seen. Funding Source Role of CASP-11 in SARS-CoV-2-induced lung pathologies and long-term immune protection Parent Project Number 5P01AI175399-02 Sub-Project ID 8361 Contact PI/Project Leader BOYAKA, PROSPER N Topic Categories Viral Immunology (VIR)