SARS-CoV-2-induced cytokine storm drives prolonged testicular injury and functional impairment in mice that are mitigated by dexamethasone

PLoS Pathog. 2025 Jan 7;21(1):e1012804. doi: 10.1371/journal.ppat.1012804. eCollection 2025 Jan.

Abstract

Compromised male reproductive health, including reduced testosterone and sperm count, is one of the long COVID symptoms in individuals recovering from mild-severe disease. COVID-19 patients display testicular injury in the acute stage and altered serum fertility markers in the recovery phase, however, long-term implications on the testis remain unknown. This study characterized the consequences of SARS-CoV-2 on testis function. The K18-hACE2 mice that survived SARS-CoV-2 infection were followed for one month after infection and the testicular injury and function markers were assessed at different stages of infection and recovery. The long-term impact of infection on key testes function-related hormones and male fertility was measured. The efficacy of inflammation-suppressing drug in preventing testicular injury was also evaluated. The morphological defects like sloughing of spermatids into the lumen and increased apoptotic cells sustained for 2-4 weeks after infection and correlated with testicular inflammation and immune cell infiltration. Transcriptomic analysis revealed dysregulation of inflammatory, cell death, and steroidogenic pathways. Furthermore, reduced testosterone levels associated with a transient reduction in sperm count and male fertility. Most testicular impairments resolved within one month of infection. Importantly, dexamethasone treatment attenuated testicular damage, inflammation, and immune infiltration. Our results implicate virus-induced cytokine storm as the major driver of testicular injury and functional impairments, timely prevention of which limits testis damage. These findings serve as a model for evaluating therapeutics in long COVID patients and may guide clinical strategies to improve male reproductive health outcomes post-SARS-CoV-2 infection.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • COVID-19 Drug Treatment
  • COVID-19* / complications
  • COVID-19* / immunology
  • Cytokine Release Syndrome* / drug therapy
  • Dexamethasone* / pharmacology
  • Dexamethasone* / therapeutic use
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • SARS-CoV-2*
  • Testis* / drug effects
  • Testis* / metabolism
  • Testis* / pathology
  • Testis* / virology
  • Testosterone

Substances

  • Dexamethasone
  • Testosterone
  • Anti-Inflammatory Agents

Grants and funding

This work was partially supported by grants NIH R21AI140248 (SV), Victoria S. And Bradley L. Geist Foundation (MDT and SV), NIH HD072380 and HD106936 (MAW), and Hawaii Community Foundation (SV). The undergraduate research internship scholarship to J.P. was supported by the National Institutes of Health (NIH), National Institute of General Medical Science, IDeA Networks of Biomedical Research Excellence (INBRE, P20GM103466). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.