SARS-CoV-2 Enters Human Leydig Cells and Affects Testosterone Production In Vitro

Lu Li, Chantal M. Sottas, Hsu Yu Chen, Yuchang Li, Haoyi Cui, Jason S. Villano, Joseph L. Mankowski, Paula M. Cannon, Vassilios Papadopoulos

Research output: Contribution to journalArticlepeer-review

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a SARS-like coronavirus, continues to produce mounting infections and fatalities all over the world. Recent data point to SARS-CoV-2 viral infections in the human testis. As low testosterone levels are associated with SARS-CoV-2 viral infections in males and human Leydig cells are the main source of testosterone, we hypothesized that SARS-CoV-2 could infect human Leydig cells and impair their function. We successfully detected SARS-CoV-2 nucleocapsid in testicular Leydig cells of SARS-CoV-2-infected hamsters, providing evidence that Leydig cells can be infected with SARS-CoV-2. We then employed human Leydig-like cells (hLLCs) to show that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 is highly expressed in hLLCs. Using a cell binding assay and a SARS-CoV-2 spike-pseudotyped viral vector (SARS-CoV-2 spike pseudovector), we showed that SARS-CoV-2 could enter hLLCs and increase testosterone production by hLLCs. We further combined the SARS-CoV-2 spike pseudovector system with pseudovector-based inhibition assays to show that SARS-CoV-2 enters hLLCs through pathways distinct from those of monkey kidney Vero E6 cells, a typical model used to study SARS-CoV-2 entry mechanisms. We finally revealed that neuropilin-1 and cathepsin B/L are expressed in hLLCs and human testes, raising the possibility that SARS-CoV-2 may enter hLLCs through these receptors or proteases. In conclusion, our study shows that SARS-CoV-2 can enter hLLCs through a distinct pathway and alter testosterone production.

Original languageEnglish (US)
Article number1198
JournalCells
Volume12
Issue number8
DOIs
StatePublished - Apr 2023

Keywords

  • ACE2
  • Leydig cells
  • SARS-CoV-2
  • SARS-CoV-2 spike pseudovectors
  • TMPRSS2
  • cinanserin
  • hamster
  • human
  • spike protein
  • testis
  • testosterone

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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