ABSTRACT
INTRODUCTION AND OBJECTIVE: Angiotensin-converting enzyme II (ACE2) is the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) to enter the host cells. The higher expression of ACE2 receptor in the testis makes it more susceptible to SARS-COV-2 infection. Recent studies have reported orchitis, impaired spermatogenesis, and presence of viruses in semen of affected men. The main objective of this study is to understand the molecular alterations induced by SARS-CoV-2 and signaling pathways dysregulated in testis. METHODS: A data mining approach was employed to identify the RNA sequencing data of human testis infected with SARS-CoV-2. The FASTQ files (PRJNA661970) were retrieved from European Nucleotide Archive (ENA) for both the infected and control groups (noninfected). RNA seq data were further processed and analyzed, using BioJupies to generate a list of differentially expressed genes (DEGs). In addition, downstream analysis was carried out, using ingenuity pathway analysis software (Qiagen, USA) to identify the differentially regulated pathways and unique non-directional gene networks. RESULTS: A total of 17,824 genes were identified in the testis of both SARS CoV-2 infected and control groups, of which 4,131 genes were differentially expressed (2,492 downregulated and 1,639 upregulated) with a fold change cut-off of±2 and P <0.05. Bioinformatic analysis revealed that molecular pathways, such as inflammatory response, reproductive system development and function, and cell-to-cell signaling and interaction, were dysregulated in testes of men infected with SARSCoV- 2. Furthermore, we have also identified enrichment of 37 DEGs in the germ cell-Sertoli cell junction signaling pathway (Table 1). CONCLUSIONS: Our bioinformatic results clearly indicate that homeostasis of germ cell-Sertoli cell junction is disturbed during SARSCoV- 2 infection, which could be a predisposing cause for impaired spermatogenesis. Future studies are warranted to understand the impact of mild, moderate, and severe SARS-CoV-2 infections on germ cell-Sertoli cell junction in both vaccinated and unvaccinated populations that may affect their reproductive performance and fertility.
ABSTRACT
INTRODUCTION AND OBJECTIVE: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) impacts male reproductive health. Nearly 50% of men who recovered from COVID-19 (without vaccination) had low levels of testosterone/ androgen and thus, are at greater risk of developing hypogonadism. Although a recent transcriptomic report showed molecular alterations in the testis of SARS-CoV-2 infected men, their impact on androgen biosynthesis and associated signaling pathways is unknown. The main objective of this study is to analyze androgen biosynthesis and signaling pathways in testis of COVID-19 patients using a bioinformatic approach. METHODS: Transcriptomic data (PRJNA661970) of testis from men infected with SARS-CoV-2 were retrieved from European Nucleotide Archive (ENA). The FASTQ files were processed using the BioJupies web tool (http://biojupies.cloud) to identify the differentially expressed genes (DEGs) in the SARS CoV-2 infected group compared to the control group (non-infected). Furthermore, DEGs were subjected to downstream analysis using Ingenuity Pathway Analysis (IPA) software (Qiagen, USA) to investigate both androgen biosynthesis and associated signaling pathways. RESULTS: Data mining and analysis resulted in the identification of 8,906 DEGs, among which 101 genes (40 downregulated and 61 upregulated) were found to be associated with hypogonadism. IPA analysis revealed that the function of enzymes involved in the androgen biosynthesis such as steroid 17a-monooxygenase, 17a-hydroxyprogesterone aldolase, steroid D-isomerase, testosterone 17b-dehydrogenase (NADP) and 3-oxo-5a-steroid 4-dehydrogenase were differentially regulated by the DEGs. Furthermore, expression of molecules regulating the androgen signaling pathways were altered in the testes of men infected with SARS-CoV-2 (Figure 1). CONCLUSIONS: Our findings demonstrate that androgen biosynthesis and associated signaling pathways important for testosterone production are dysregulated in testis of men infected with COVID-19. This may result in prolonged testosterone deficiency leading to hypogonadism in COVID-19 patients. Future studies are warranted to assess the impact of SARS-CoV-2 on accessory sex glands (especially prostrate) which are under the regulation of androgen signaling pathway.