The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection

Abstract

The serious coronavirus disease-2019 (COVID-19) was first reported in December 2019 in Wuhan, China. COVID-19 is an infectious disease caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Angiotensin converting enzyme 2(ACE2) is the cellular receptor for SARS-CoV-2. Considering the critical roles of testicular cells for the transmission of genetic information between generations, we analyzed single-cell RNA-sequencing (scRNA-seq) data of adult human testis. The mRNA expression of ACE2 was expressed in both germ cells and somatic cells. Moreover, the positive rate of ACE2 in testes of infertile men was higher than normal, which indicates that SARS-CoV-2 may cause reproductive disorders through pathway activated by ACE2 and the men with reproductive disorder may easily to be infected by SARS-CoV-2. The expression level of ACE2 was related to the age, and the mid-aged with higher positive rate than young men testicular cells. Taken together, this research provides a biological background of the potential route for infection of SARS-CoV-2 and may enable rapid deciphering male-related reproductive disorders induced by COVID-19.

Keywords: ACE2; COVID-19; reproductive disorder; scRNA-seq; testicular cells.

Figure 1

scRNA‐seq analysis of ACE2 in human testicular cells. A, Expression patterns (violin plot) showing the mRNA expression of ACE2 in the 12 clusters of the mid‐aged. The Sertoli cells are the highest positive cluster. B, The violin plot of mRNA expression of ACE2 across all cell types of the young group. C, UMAP plot showing the mRNA expression ACE2 across clusters of mid‐aged. The Sertoli cells (SOX9) are the highest ACE2‐positive cells, SSCs with the highest ACE2 positive rate in Germ cells (DDX4), and some Leydig cells (VIT) are positive. D, In young group, the ACE2‐positive cells shown in the Germ cells, Sertoli cells and Leydig cells. E, The percentage of ACE2‐positive cells in different type cells in mid‐aged, Sertoli cells with the highest positive cluster (over 90%). F, Sertoli cells are the highest cluster with ACE2‐positive cells in the young group

Figure 2

ACE2 expression in health and male infertility donors. A, UMAP plots showing the characteristics of N (left), OA (middle) and NOA (right) donors. The health are lower than that donors with reproductive dysfunction. B, tSNE plot of testicular cells to visualize cell‐type clusters (60 y old). The violin plot of ACE2 gene expression across all cell types in testis. C, tSNE plot of testicular cells to visualize cell‐type clusters (30 y old), and violin plot of ACE2 gene expression across all cell types in testis. D, The percentage of ACE2‐positive cells of different ages. In 30‐y‐old, men with the highest ACE2 positive rate, while about 20 y was relatively low, and the lowest ratio was the 60‐y‐old. E, ACE2 is interacting with proteins of inflammation‐related HTR3A and tumorigenesis‐related CHRNA1