Implications of RNA Viruses in the Male Reproductive Tract: An Outlook on SARS-CoV-2

Abstract

Emerging viral infections continuously pose a threat to human wellbeing. Several RNA viruses have managed to establish access to the male reproductive tract and persist in human semen. The sexual transmission of the virus is of critical public concern. The epidemiological inferences are essential to understand its complexity, particularly the probability of viral transmission from asymptomatic patients or those in the incubation period or from the patient who was previously infected and now fully recovered. From the clinical perspective, negative impacts in the male reproductive tract associated with RNA virus infection have been described, including orchitis, epididymitis, impaired spermatogenesis, and a decrease in sperm quality, which can affect male fertility at different time intervals. The disruption of anatomical barriers due to inflammatory responses might enable the viral invasion into the testis, and the immune privilege status of testes might facilitate a sustained persistence of the virus in the semen. In this review, the current knowledge about other RNA viruses that affect male reproductive health provides the framework to discuss the impact of the SARS-CoV-2 pandemic. The molecular mechanisms, sexual transmission, and viral impacts for mumps, HIV, Zika, and Ebola viruses are explored. We discuss the currently available information on the impact of SARS-CoV-2 and its sequelae in the male reproductive tract, particularly regarding presence in semen, its impact on sexual organs, and sperm quality. To date, no sexual transmission of SARS-CoV-2 has been reported, whereas the identification of viral particles in semen remains conflicting. In the purview of the earlier conducted analyses, it is essential to investigate further the long-term health impacts of SARS-CoV-2 on the male reproductive tract.

Keywords: COVID-19; RNA virus; SARS-CoV-2; male infertility; seminal fluid; sexual transmission.

FIGURE 1

Male reproductive tract, spermatogenesis, and SARS-CoV-2 receptor expression. (A) Scheme of the male reproductive system composition. The organs for which ACE2 and TMPRSS2 expression has been reported at RNA and/or protein level are indicated. (B) The testes are composed mainly by seminiferous tubules (up to 90% of the testis volume). Immotile sperm flow from the lumen of the seminiferous tubules into the epididymis via the rete testis. During the passage through the epididymis to the vas deferens, the spermatozoa mature and acquire their motility. (C) A transverse section of seminiferous tubules is illustrated. The cells for which ACE2 and TMPRSS2 expression has been reported at the RNA and/or protein level are indicated. Spermatogenesis occurs within the seminiferous tubules. Spermatogonia (diploid primordial germ cells) are located near the basal lamina of the seminiferous tubules. When spermatogonia divide by a first mitotic division, they produce diploid primary spermatocytes. Half of these primary spermatocytes will remain near the basal lamina dividing mitotically to allow the production of new spermatozoa during the whole male’s reproductive lifespan. The other half migrate toward the lumen of the seminiferous tubules and undergo meiosis I, generating haploid secondary spermatocytes, which divide through meiosis II to produce haploid spermatids. A final stage called spermiogenesis produces mature sperm cells (spermatozoa) capable of fertilizing an egg. Leydig cells produce the hormone testosterone.

FIGURE 2

SARS-CoV-2 cell entry mechanism. The SARS-CoV-2 cycle commences by binding the envelope Spike protein to the receptor (ACE2). When recognizing the ACE2 receptor, the RBD stands up to bind the receptor. At the cell membrane, SARS-CoV-2 recruits TMPRSS2, a protease that facilitates viral entry, cleaving S1/S2 site of Spike. Two entry pathways have been described for SARS-CoV-2 cell entry: (1) The presence of proteases triggers the fusion of viral and host membranes. (2) The virus can be endocyted and then released by activation of cathepsin L. Through either entry mechanism, the RNA genome is released into the cytosol, where it is translated and replicated to generate new virions.