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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Epublish 12 citations

PubMed: 37200377 DOI: 10.1371/journal.ppat.1011409

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury.

PLoS Pathog 19(5):e1011409

Authors: Stefanos Giannakopoulos, Daniel P Strange, Boonyanudh Jiyarom, Omar Abdelaal, Aaron W Bradshaw, Vivek R Nerurkar, Monika A Ward, Jackson Bakse, Jonathan Yap, Selena Vanapruks, William A Boisvert, Michelle D Tallquist, Cecilia Shikuma, Hooman Sadri-Ardekani, Philip Clapp, Sean V Murphy, 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.
  • Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
  • Department of Urology, Faculty of Medicine, Zagazig University, Egypt.
  • Department of Urology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
  • 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, Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.

Abstract

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

MeSH

Infections, Host-Parasite Interactions, Cells, Sars Virus, Bystander Effect, Covid-19, Sars-Cov-2

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