The Severity of SARS-CoV-2 Infection in K18-hACE2 Mice is Attenuated by a Novel Steroid-Derivative in a Gender-Specific Manner

Authors

Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.Follow
Chandra Shekhar Bakshi, Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, USA.Follow
Emma Blackham, Sygnature Discovery Limited, Nottingham, UK.
Gerald E. Duhamel, Department of Biomedical Sciences and New York State Animal Health Diagnostic Center and Section of Anatomic Pathology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Allan Jordan, Sygnature Discovery Limited, Nottingham, UK.
Padmini Salgame, Department of Medicine, Division of Infectious Diseases and The Center for Emerging Pathogens, Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
Melinee D'silva, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Mohammad Y. Khan, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Jerry Nadler, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.Follow
Rakhee Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.

Author Type(s)

Faculty

DOI

10.1111/bph.16155

Journal Title

British Journal of Pharmacology

First Page

2677

Last Page

2693

Document Type

Article

Publication Date

10-1-2023

Department

Pharmacology

Second Department

Pathology, Microbiology and Immunology

Third Department

Medicine

Abstract

BACKGROUND AND PURPOSE: COVID-19 infections caused by SARS-CoV-2 disseminated through human-to-human transmission can evoke severe inflammation. Treatments to reduce the SARS-CoV-2-associated inflammation are needed and are the focus of much research. In this study, we investigated the effect of N-ethyl-N'-[(3β,5α)-17-oxoandrostan-3-yl] urea (NEOU), a novel 17α-ketosteroid derivative, on the severity of COVID-19 infections. EXPERIMENTAL APPROACH: Studies were conducted in SARS-CoV-2-infected K18-hACE2 mice. KEY RESULTS: SARS-CoV-2-infected K18-hACE2 mice developed severe inflammatory crises and immune responses along with up-regulation of genes in associated signalling pathways in male more than female mice. Notably, SARS-CoV-2 infection down-regulated genes encoding drug metabolizing cytochrome P450 enzymes in male but not female mice. Treatment with NEOU (1 mg·kg ·day ) 24 or 72 h post-viral infection alleviated lung injury by decreasing expression of genes encoding inflammatory cytokines and chemokines while increasing expression of genes encoding immunoglobins. In situ hybridization using RNA scope™ probes and immunohistochemical assays revealed that NEOU increased resident CD169 immunoregulatory macrophages and IBA-1 immunoreactive macrophage-dendritic cells within alveolar spaces in the lungs of infected mice. Consequentially, NEOU reduced morbidity more prominently in male than female mice. However, NEOU increased median survival time and accelerated recovery from infection by 6 days in both males and females. CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that SARS-CoV-2 exhibits gender bias by differentially regulating genes encoding inflammatory cytokines, immunogenic factors and drug-metabolizing enzymes, in male versus female mice. Most importantly, we identified a novel 17α-ketosteroid that reduces the severity of COVID-19 infection and could be beneficial for reducing impact of COVID-19.

Recommended Citation

Gupte, S. A., Bakshi, C. S., Blackham, E., Duhamel, G. E., Jordan, A., Salgame, P., D'silva, M., Khan, M. Y., Nadler, J., & Gupte, R. (2023). The Severity of SARS-CoV-2 Infection in K18-hACE2 Mice is Attenuated by a Novel Steroid-Derivative in a Gender-Specific Manner. British Journal of Pharmacology, 180 (20), 2677-2693. https://doi.org/10.1111/bph.16155