Journal Article Epublish 6 citations
PubMed: 39775442 DOI: 10.1371/journal.ppat.1012804
SARS-CoV-2-induced cytokine storm drives prolonged testicular injury and functional impairment in mice that are mitigated by dexamethasone.
PLoS Pathog 21(1):e1012804
Authors: Stefanos Giannakopoulos, Jin Pak, Jackson Bakse, Monika A Ward, Vivek R Nerurkar, Michelle D Tallquist, Saguna Verma
Affiliations
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
- Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
- Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
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
Cytokines, Cells, Sars-Cov-2, Fertility, Dexamethasone, Host-Parasite Interactions, Reproductive Health, Sperm Count, Recycling, Cytokine Release Syndrome, Testosterone, Covid-19, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Spermatozoa, Testis, Infections