Journal Article

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

Strange, Daniel P., Shikuma, Cecilia, Giannakopoulos, Stefanos, Jiyarom, Boonyanudh, Tallquist, Michelle D., Vanapruks, Selena, Bakse, Jackson, Boisvert, William A., Yap, Jonathan, Verma, Saguna, Clapp, Philip, Murphy, Sean V., Nerurkar, Vivek R., Sadri-Ardekani, Hooman, Abdelaal, Omar, Bradshaw, Aaron W., Ward, Monika A.

2023

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ACE2 / Analysis / Angiotensin-converting enzyme 2 / Animals / Antigens / Biology and life sciences / Bystander Effect / Cell culture / Cell death / Cell viability / COVID-19 / COVID-19 - metabolism / Cytokine storm / Cytokines / Env protein / Enzymes / Epithelial cells / Epithelium / Exposure / Genetic engineering / Health aspects / Humans / Infection / Infections / Inflammation / Inflammation - metabolism / Inflammatory response / Injury prevention / Leydig cells / Male / Medicine and health sciences / Mice / Mice, Transgenic / Nucleocapsids / Organoids / Proteins / Research and Analysis Methods / SARS-CoV-2 / Seminiferous tubule / Sertoli cells / Severe acute respiratory syndrome coronavirus 2 / Signs and symptoms / Spermatogonia / Testes / Testis / Testosterone / TLR2 protein / Toll-like receptors / Transgenic mice / Tumor necrosis factor-TNF / Viral antigens / Viral diseases / Viral envelope proteins / Virus diseases / Viruses