Article Impact Level: HIGH Data Quality: STRONG Summary of Frontiers in Cellular and Infection Microbiology, 15, 1538461. https://doi.org/10.3389/fcimb.2025.1538461 Dr. Salmo Azambuja de Oliveira et al.
Points
- The SARS-CoV-2 virus directly targets and infects testosterone-producing Leydig cells in the testes by binding to the highly expressed ACE2 receptors on their surface.
- After infection, the virus hijacks the cell’s cholesterol and lipid metabolism pathways, using the raw materials intended for hormone synthesis to replicate its own viral particles.
- This viral appropriation of the cell’s machinery results in a significant reduction in the production of key steroidogenic proteins and the hormone testosterone, which explains clinical observations.
- Infected Leydig cells shift from their normal hormone-producing function to an immunological one, releasing large quantities of pro-inflammatory cytokines that contribute to local tissue damage.
- These findings help explain the low testosterone and altered cholesterol levels seen in male patients with severe COVID-19 and suggest a mechanism for their increased vulnerability.
Summary
A study investigating the testicular impact of SARS-CoV-2 infection in K18-hACE2 transgenic mice provides a molecular basis for the clinically observed hypogonadism and higher mortality in male COVID-19 patients. Researchers sought to evaluate the response of testicular macrophages, Leydig cell steroidogenesis, and lipid metabolism following viral infection. The investigation confirmed that Leydig cells, which express high concentrations of the hACE2 receptor, are a direct target for SARS-CoV-2. Immunolocalization demonstrated the presence of both viral spike and nucleocapsid proteins within these cells.
Methodological analysis using light and electron microscopy, immunolocalization, Western blot, and RT-qPCR revealed significant testicular pathology. Infection led to an upregulation of the viral recognition receptor RIG-I and a marked pro-inflammatory response, evidenced by increased expression of TNF-α, IL-1β, and IL-6, as well as a rise in CD68+ and CD163+ macrophages. Concurrently, steroidogenesis was significantly impaired, demonstrated by reduced expression of steroidogenic factor-1 (Sf1) and lower testosterone levels. The study found viral particles within lipid droplets, indicating the virus co-opts the cell’s lipid machinery for its own replication.
The findings conclude that SARS-CoV-2 directly infects testicular Leydig cells, transforming their function from steroidogenic to immunological. The virus hijacks cholesterol pathways essential for testosterone synthesis to facilitate its replication, resulting in the accumulation of intracellular lipids despite suppressed steroid hormone production. The increased expression of lipid metabolism genes Srebp, Dgat1, and Scarb1 supports this. This mechanism helps explain the low testosterone and altered HDL levels seen in men with severe COVID-19 and suggests that therapies targeting lipid metabolism could be a potential strategy to inhibit viral action.
Link to the article: https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1538461/full
References De Oliveira, S. A., Da Silva, A. A. S., Hinton, B. T., Gomes, G. F., Cunha, T. M., Cerri, P. S., & Sasso-Cerri, E. (2025). SARS-CoV-2 exploits steroidogenic machinery, triggers lipid metabolism for viral replication and induces immune response in Leydig cells of K18-hACE2 mice. Frontiers in Cellular and Infection Microbiology, 15, 1538461. https://doi.org/10.3389/fcimb.2025.1538461
