ORIGINAL RESEARCH article
Front. Cell. Infect. Microbiol.
Sec. Molecular Viral Pathogenesis
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1538461
This article is part of the Research TopicPerspectives in Molecular Viral Pathogenesis: 2025View all 4 articles
SARS-CoV-2 exploits steroidogenic machinery, triggers lipid metabolism for viral replication and induces immune response in Leydig cells of K18-hACE2 mice
Provisionally accepted
Salmo Azambuja de Oliveira1
André Acácio Souza da Silva1
Barry Thomas Hinton2
Giovanni Freitas Gomes3
Thiago Mattar Cunha4
Paulo Sergio Cerri5
ESTELA SASSO CERRI5*- 1Federal University of São Paulo, São Paulo, São Paulo, Brazil
- 2School of Medicine, University of Virginia, Charlottesville, Virginia, United States
- 3University of São Paulo, Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil
- 4University of Ribeirão Preto, Ribeirão Preto, Sao Paulo, Brazil
- 5São Paulo State University, São Paulo, São Paulo, Brazil
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Background: During COVID-19 pandemic, men had reduced serum testosterone and higher mortality rate than women. Variations in high density lipoprotein (HDL) levels were detected in severe COVID-19 individuals. We evaluated the response of testicular macrophages, steroidogenic activity and lipid metabolism of Leydig cells in SARS-CoV-2-infected K18-hACE2 mice.: Testes were analyzed under light and electron microscope. Immunolocalization of human angiotensin converting enzyme (hACE2) and viral proteins (spike and nucleocapsid) were evaluated in association with the expression of viral recognition receptor, Rigi. Steroidogenesis was evaluated by the expression of steroidogenic factor-1 (Sf1), and the immunolocalization of steroidogenic proteins and testosterone. Pro-inflammatory (TNF-α, IL-1β, IL-6), anti-inflammatory (IL-10) cytokines, macrophages (CD68 and CD163) and macrophage inhibitory factor (MIF) were detected by immunolocalization and Western blot. The expression of lipid metabolism genes (Srebp, Dgat1 and Scarb1) were investigated by RT-qPCR. Results: In the infected animals, the Leydig cells showed enhanced immunolocalization of hACE2, spike and nucleocapsid. The expression of Rigi, pro-inflammatory cytokines and number of macrophages increased, confirming viral infection. Sf1 expression, steroidogenic proteins and testosterone were reduced whereas the expression of Dgat1, Srebp and Scarb1 increased. Lipid droplets-enriched Leydig cells and viral particles in lipids were observed. The infected Leydig cells also showed enhanced pro-inflammatory cytokines immunolabeling. Conclusion: SARS-CoV-2 infects Leydig cells, activates its immune response and impairs steroidogenesis. The virus uses the steroidogenic machinery and induces lipid metabolism pathways for its survival and replication in these cells. These findings support the low testosterone and HDL levels in men with severe COVID-19.
Keywords: COVID-19, Testosterone, Cholesterol, Lipogenesis, Nucleocapsid, Cytokines, Macrophages, Electron microscopy
Received: 02 Dec 2024; Accepted: 24 Apr 2025.
Copyright: © 2025 de Oliveira, da Silva, Hinton, Gomes, Cunha, Cerri and CERRI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: ESTELA SASSO CERRI, São Paulo State University, São Paulo, 01049-010, São Paulo, Brazil
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