SARS-CoV-2 infection reduces the number of spermatogonial stem cells and dysregulates the transcriptional landscape of the human testis

SARS-CoV-2 coronavirus emerged in 2019, leading to the Coronavirus disease 2019 (COVID-19). Expression of viral entry factors such as ACE2 and TMPRSS2 is higher in the testis, particularly in Sertoli cells, Leydig cells, and spermatogonia. To understand COVID-19's impact on testicular cell populations and gene expression, we analyzed testicular tissue samples from 28 COVID-19 patients and compared them with 23 non-diseased controls. COVID-19 samples showed increased immune cell infiltration, thrombosis, and reduced numbers of testicular cells. There was a significant decrease in Sertoli cells and spermatogonial stem cells (SSC) among COVID-19 patients, associated with high levels of DNA damage and apoptosis in these cell types. To explore the pathways through which the virus affects testicular function, we profiled 112,657 single-nucleus transcriptomes from the testes of 4 COVID-19 patients and 4 controls. We found that COVID-19 infection alters multiple transcriptome clusters and induces a new COVID-19-specific cluster. To confirm that these transcriptome changes are COVID-19-specific, we compared our results with those from the brains of patients with COVID-19 and influenza. We observed an average of 144 dysregulated genes unique to COVID-19, regardless of tissue type. Lastly, we examined whether the SSC phenotype seen in fatal COVID-19 cases was also present in recovered patients. Indeed, recovered patients also exhibited high DNA damage and a reduced SSC population at 3, 6, and 12 months post-infection. Additionally, embryos derived from recovered patients’ sperm showed lower fertilization rates compared to control-derived embryos and fewer live births. Overall, our findings demonstrate that SARS-CoV-2 disrupts spermatogenesis, alters the transcriptional landscape, and affects human testicular architecture and function well after the acute phase of infection, with potential long-term consequences for male fertility.