Multiple expression assessments of ACE2 and TMPRSS2 SARS-CoV-2 entry molecules in the urinary tract and their associations with clinical manifestations of COVID-19

Abstract

Background: Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. From previously published evidence, ACE2 and TMPRSS2, are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Meanwhile, increased expression of pro-inflammatory cytokines, or a "cytokine storm," is associated with multiple organ dysfunction syndrome that is often observed in critically ill patients. Methods: We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially under specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2 specific signature. Results: Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis, and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were remarkably concentrated in endothelial cells, macrophages, and spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging mechanisms via autoimmune attacks. Conclusions: This study provided new insights into the pathogenicity mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.

Potential mechanisms of SARS‐CoV‐2 action on male gonadal function and fertility: Current status and future prospects

“…It is implicit that co-expression of ACE2 and transmembrane protease F I G U R E 1 Possible effects of SARS-CoV-2 on the function of main types of testicular cells by an altered ACE-2 signalling pathway. ACE2: angiotensin-converting enzyme-2; ASA: anti-sperm antibody serine 2 (TMPRSS2) is essential for involvement of a tissue by SARS-CoV-2, and a recent study has shown that the testis has a high coexpression of ACE2 and TMPRSS2 (Ren et al, 2020).…”

“…A previous study in rodents with autoimmune orchitis showed that an increase in the serum level of IL-6 and its receptor, a cytokine that regulates inflammation and immune response, could be associated with pathogenesis of autoimmune orchitis (Rival et al, 2006). It has been reported that more severe cases of COVID-19 are accompanied by a high level of IL-6, and its receptors are highly expressed in testicular cells (Ren et al, 2020;Shen et al, 2020). This can justify the probable male gonadal involvement and a subsequent possibility of orchitis as a complication of SARS-CoV-2.…”

“…There are two main reasons why increased sperm DFI can be expected in patients with COVID-19. First, male gonadal involvement and a subsequent inflammation in testes are possible complications of SARS-CoV-2 (Fan et al, 2020;Ma et al, 2020;Ren et al, 2020;Rival et al, 2006;Xu et al, 2006). Inflammation can lead to excessive production of ROS, and this product can lead to sperm DNA damage (Anifandis et al, 2020;Evenson & Wixon, 2006;Homa et al, 2019;Karimi et al, 2020).…”

Evidence of SARS-CoV2 entry protein ACE2 in the human nose and olfactory bulb

“…High ACE2 and TMPRSS2 expressions have been documented in the respiratory, gastrointestinal, and reproductive system [11,12]. Focusing on the upper respiratory tract, increased ACE2 and TMPRSS2 are found in the respiratory and olfactory mucosa.…”

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

“…Shen et al report similar findings in their pre-print [24]. Another pre-print examining ACE2 expression throughout the urinary tract reported higher expression in testicular gametocytes and in renal proximal tubules [25]. Finally, Wu et al report in their pre-print, the relationship between androgen receptor activation and ACE2 and TMPRSS2 expression, and how this may contribute to the higher mortality from COVID-19 in males [26].…”