scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells

Abstract

In December 2019, a novel coronavirus (SARS-CoV-2) was identified in COVID-19 patients in Wuhan, Hubei Province, China. SARS-CoV-2 shares both high sequence similarity and the use of the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV). Several studies have provided bioinformatic evidence of potential routes of SARS-CoV-2 infection in respiratory, cardiovascular, digestive and urinary systems. However, whether the reproductive system is a potential target of SARS-CoV-2 infection has not yet been determined. Here, we investigate the expression pattern of ACE2 in adult human testes at the level of single-cell transcriptomes. The results indicate that ACE2 is predominantly enriched in spermatogonia and Leydig and Sertoli cells. Gene Set Enrichment Analysis (GSEA) indicates that Gene Ontology (GO) categories associated with viral reproduction and transmission are highly enriched in ACE2-positive spermatogonia, while male gamete generation related terms are downregulated. Cell-cell junction and immunity-related GO terms are increased in ACE2-positive Leydig and Sertoli cells, but mitochondria and reproduction-related GO terms are decreased. These findings provide evidence that the human testis is a potential target of SARS-CoV-2 infection, which may have significant impact on our understanding of the pathophysiology of this rapidly spreading disease.

SARS‐CoV‐2, testosterone and frailty in males (PROTEGGIMI): A multidimensional research project

“…As a consequence, ACE2 expression in human testes -which has been also found at the protein levels 18 -suggests that SARS-CoV-2 could eventually infect the male testis, with a consequential risk in terms of male reproductive dysfunction, because of a disruption of spermatogenesis if spermatogonia were infected by the virus 16 .…”

“…Conversely, early spermatocytes, late spermatocytes, spermatids and somatic cells express very low levels of ACE2 16 . Of relevance, the enrichment of ACE2 in Leydig and Sertoli cells demonstrated a 3-fold higher percentage compared to ACE2-expressing cells among type II alveolar epithelial cells (AT2) in human lungs 16 . The previously described high ACE2 expression in…”

“…Recently, ACE2 expression levels have been demonstrated to be higher in males than in females, at least in the lungs 15 . Furthermore, a more detailed analysis of the expression pattern of ACE2 in adult human testes, utilising uniform manifold approximation and projection (UMAP) and marker gene analysis, also indicates that ACE2 is predominantly enriched in spermatogonia, Leydig and Sertoli cells 16 ; therefore, it has been speculated that the human testis may be a further potential route of SARS-CoV-2 infection. Conversely, early spermatocytes, late spermatocytes, spermatids and somatic cells express very low levels of ACE2 16 .…”

“…Furthermore, a more detailed analysis of the expression pattern of ACE2 in adult human testes, utilising uniform manifold approximation and projection (UMAP) and marker gene analysis, also indicates that ACE2 is predominantly enriched in spermatogonia, Leydig and Sertoli cells 16 ; therefore, it has been speculated that the human testis may be a further potential route of SARS-CoV-2 infection. Conversely, early spermatocytes, late spermatocytes, spermatids and somatic cells express very low levels of ACE2 16 . Of relevance, the enrichment of ACE2 in Leydig and Sertoli cells demonstrated a 3-fold higher percentage compared to ACE2-expressing cells among type II alveolar epithelial cells (AT2) in human lungs 16 .…”

“…Furthermore, SARS-CoV-2 was found to utilise transmembrane serine protease 2 (TMPRSS2) for viral S protein priming 19 . TMPRSS2 expression has been found to be concentrated in spermatogonia and spermatids 16 . Interstingly: TMPRSS2 is an androgen-regulated cell surface protease, which had been previously found to be predominantly expressed in prostate epithelium 20 .…”