Re: Hanbing Song, Bobak Seddighzadeh, Matthew R. Cooperberg, Franklin W. Huang. Expression of ACE2 and TMPRSS2, the SARS-CoV-2 Receptor and Co-Receptor, in Prostate Epithelial Cells. Eur Urol. In press DOI: 10.1016/j.eururo.2020.04.065

We read with great interest the commendable article by Song et al [1] and congratulate the authors for bringing this timely report to the field of scientific research on coronavirus disease 19 (COVID-19). Daily data from different countries and continents provide evidence that approximately 60% of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are male, with a significant difference in the rate of severe cases and lethality between adult males and females [2]. In an attempt to explain these differences, a number of hypotheses have been proposed on the basis of biological features, androgenic signaling, and lifestyle habits [3].

Song et al investigated gene co-expression of TMPRSS2 and ACE2 in 24 519 human prostate epithelial cells and found that 0.40% of hillock cells and 0.61% of club cells co-expressed TMPRSS2 and ACE2 [1]. Since hillock and club cells were originally identified in lung, the authors also analyzed TMPRSS2 and ACE2 co-expression in human lung secretory cells, human lung club cells, and murine lung club cells. Although no gender differences in TMPRSS2 expression were detected in human lung cells, higher TMPRSS2 and ACE2 co-expression was found in male pneumocytes I/II compared to female cells. This is an important article pointing out an epidemiological dilemma in the COVID-19 pandemic. However, some issues deserve discussion.

First, the authors focused their analysis on only two genes, TMPRSS2 and ACE2, which are currently considered crucial elements for SARS-CoV-2 entry into host cells. Since TMPRSS2 expression has been reported to be androgen-dependent and the ACE2 gene is located on the X chromosome, both genes may play an important role in mediating gender-specific effects in viral infection [3]. The scientific community is showing strong interest in TMPRSS2 and ACE2, and a clinical trial evaluating the efficacy of two TMPRSS2 inhibitors (nafamostat and camostat) in the treatment of COVID-19 is currently underway in Japan (Fig. 1 A,B) [4]. Nonetheless, several other gender-linked genes could be involved in driving dimorphic immune responses to viral infections [5]. More specifically, a wide number of genes such as SOX9 and SRY (linked to the Y chromosome) and FOXP3, TLR7, XIST, IL10, IL13, and IL14 (linked to the X chromosome) could have unexpected roles in differential gender-related immune responses to SARS-CoV-2 [5]. Second, an important number of unknown nongenetic determinants could be involved in gender differences in an in vivo setting, especially for severity and lethality rates.

Fig. 1.

(A) Regulation of TMPRSS2 gene transcription and (B) SARS-CoV-2 entry into target cells. (A) The androgen receptor gene and ACE2 gene are located on Xq12 and Xp22.2, respectively. Testosterone and dihydrotestosterone stimulate androgen receptor activity. Activated androgen receptor regulates transcription of the TMPRSS2 gene. TMPRSS2:ERG gene fusion is associated with prostate cancer development. (A) SARS-CoV-2 engages ACE2 as the entry receptor and uses TMPRSS2 for spike protein priming. Serine protease inhibitors such as camostat mesylate can inhibit TMPRSS2 and partly block cell entry driven by the SARS-CoV-2 spike protein.

In summary, the study provides important data regarding the possible association between TMPRSS2 and ACE2 co-expression and sex differences in COVID-19. We believe that specific data regarding TMPRSS2 and ACE2 expression in patients experiencing different clinical manifestations could suggest new directions for present and future research on COVID-19.

Evidence regarding COVID-19 is being collected each day. We hope that a better comprehension of the role of X-linked and Y-linked genes will be helpful in unveiling the reasons behind the epidemiological dilemma of gender differences in COVID-19 and in identifying novel therapeutic options, which is an urgent need in the battle against SARS-CoV-2.



 Conflicts of interest: The authors have nothing to disclose.