New research from Brazil sheds light on a critical mechanism by which the COVID-19 virus, SARS-CoV-2, compromises male reproductive health. The study indicates that the virus specifically targets and manipulates the cellular machinery within testicular cells responsible for testosterone synthesis and lipid processing. This interaction allows SARS-CoV-2 to repurpose essential cellular components and metabolic pathways, including those involving cholesterol, for its own proliferation, inadvertently disrupting the normal physiological functions of these cells. This groundbreaking discovery offers valuable insights into the observed hormonal imbalances, such as reduced testosterone levels, and altered cholesterol profiles in men experiencing severe forms of COVID-19.

Researchers at the Araraquara School of Dentistry at São Paulo State University (FOAr-UNESP), in collaboration with the Ribeirão Preto School of Medicine at the University of São Paulo (FMRP-USP), conducted this investigation using transgenic mouse models. These models, engineered to express the human ACE2 receptor—the primary entry point for SARS-CoV-2 into human cells—mimic the human COVID-19 disease progression. The study marks the first time that viral particles have been observed within the lipid inclusions and testosterone-producing organelles of Leydig cells in the testicles. The findings illuminate the intricate viral strategy of exploiting host cell resources and also detail how this interference impacts the functional capacity of these crucial testicular cells.

Dr. Estela Sasso-Cerri, a professor at FOAr-UNESP and the lead coordinator of this study, highlighted the significant role of Leydig cells in this viral hijacking. She explained that these cells possess high concentrations of the ACE2 receptor, making them an accessible and attractive target for SARS-CoV-2. Once infected, the virus co-opts the cells' lipid metabolism pathways and internal structures, including those dedicated to synthesizing steroid hormones, to facilitate its own replication. This parasitic activity directly impairs the Leydig cells' primary function of producing testosterone. Furthermore, these cells are naturally rich in cholesterol, a vital precursor for testosterone, making them an ideal environment for viral multiplication, which requires significant lipid resources for the formation of new viral particles.

The research demonstrated that SARS-CoV-2 fundamentally alters the lipid metabolism within Leydig cells. The virus diverts cholesterol, which would typically be used for testosterone synthesis, towards its own replication. This explains why, despite lower testosterone levels, infected Leydig cells were observed to be rich in lipids, indicating an increased uptake of cholesterol driven by viral demand for its assembly. Beyond metabolic alterations, the study also uncovered a shift in the functional identity of these cells. Post-infection, Leydig cells largely ceased their steroid hormone production and instead adopted an immunological role.

Salmo Azambuja de Oliveira, a student from the Structural and Functional Biology Program (BEF) at the Federal University of São Paulo (UNIFESP) and the lead author of the study, detailed how the viral presence induced Leydig cells to secrete substantial amounts of pro-inflammatory cytokines. This is an activity not typically associated with these cells and likely contributes to the reduction in testosterone output. The overall understanding gained from these observations provides a clearer picture of the cellular and molecular mechanisms underlying testicular endocrine dysfunction triggered by viral infection. These findings are particularly relevant for understanding why men might be more susceptible to severe COVID-19 outcomes and exhibit higher mortality rates compared to women. Additionally, this research opens avenues for identifying new biomarkers to assess disease severity and developing targeted therapies, potentially utilizing lipid-modulating drugs, to counteract the viral impact on lipid metabolism and inhibit its spread.