COVID-19 and human spermatozoa—Potential risks for infertility and sexual transmission?
TLDR: scroll to end
As COVID-19 infections wreak havoc across the globe, attention has rightly been focused on the vital organ systems (lung, kidney and heart) that are vulnerable to viral attack and contribute to the acute pathology associated with this disease.
However, we should not lose sight of the fact that COVID-19 will attack any cell type in the body expressing ACE2 – including human spermatozoa.
These cells possess the entire repertoire of receptors (AT1R, AT2R, MAS) and ligand processing enzymes (ACE1 and ACE2) needed to support the angiotensin signalling cascade.
The latter not only provides COVID-19 with a foothold on the sperm surface but may also promote integration, given the additional presence of a range of proteases (TMPRSS2, TMPRSS11B, TMPRSS12, furin) capable of promoting viral fusion.
This article reviews the roles played by these various cellular constituents in maintaining the vitality of human spermatozoa and their competence for fertilization. The reproductive consequences of a viral attack on these systems, in terms of fertility and the risk of sexual transmission, are currently unknown.
However, we should be alive to the possibility that there may be reproductive consequences of COVID-19 infection in young males that go beyond their capacity to survive a viral attack.
If only someone warned you.
A recent report published in JAMA Network Open revealed that in an analysis 38 semen samples from COVID-19 patients, 6 (four at the acute stage of infection and, alarmingly, two who were recovering) tested positive for the virus by RT-PCR.1 Importantly, at this point, we have no idea whether the actual virus was viable and infectious. Nevertheless, the possibility that this coronavirus could have a pathophysiological impact on the testes was suggested by additional data indicating that active COVID-19 infection dramatically reduced the testosterone-to-LH ratio, suggesting a significant impact on the responsiveness of Leydig cells to LH stimulation.2
In many ways, we should not be surprised by these observations because the blood-testes barrier is known to offer little defense against viral invasion, given the wide range of pathogenic viruses (HIV, hepatitis, mumps, papilloma) that are known to be capable of damaging the testes and rendering the host infertile. Furthermore, the spike protein that gives the COVID-19 virus its corona is known to target ACE2 (angiotensin-converting enzyme 2), which is highly expressed by several cell types in the testes including Leydig cells, Sertoli cells, and the germ line.
As a result of these factors, several opinion pieces have been published already, raising the possibility of testicular damage and infertility consequent to COVID-19 infection.2–4 However, it is also possible that the virus could gain access to male germ cells once they leave the testes, either in the epididymis or following ejaculation. In this Opinion Article, I shall be focusing on this post-testicular route of infection pointing out, for the first time, that the mature spermatozoon has all of the machinery needed to bind this virus, fuse with it, and even achieve reverse transcription of the viral RNA into proviral DNA. Such considerations raise the possibility that spermatozoa could act as potential vectors of this highly infectious disease. This happens in insects5—why not us?
“Furthermore, the spike protein that gives COVID-19 virus its corona is known to target ACE2…”
“However, it is also possible that the virus could gain access to male germ cells once they leave the testes… following ejaculation.”
to put it in terms you degenerates can understand
It has been known for many years that the human sperm surface expresses ACE.
They have been known for some time to express a testicular variant of ACE1, which converts the inactive decapeptide hormone, angiotensin I, to the active octapeptide, angiotensin II (Figure 1). Testicular ACE corresponds to the ancestral non-duplicated form of the ACE gene; it lacks multiple 5′ exons and has a distinct N-terminus: biochemically however, it performs exactly the same function as somatic ACE1.10 Spermatozoa also express ACE2, which converts angiotensin II to angiotensin (1-7). Reference to the human sperm proteome also indicates that these cells possess the two known receptors for angiotensin II: angiotensin II type-1 receptor (AT1R) and (angiotensin II type-2 receptor) (AT2R). Furthermore, a recent publication has revealed that human spermatozoa also express the angiotensin (1-7) MAS receptor.9 These cells therefore possess the complete repertoire of ligand-processing enzymes and receptors needed to support angiotensin signaling pathways, raising questions about the physiological roles these pathways play and how they might intersect with COVID-19 (Figure 1).
Germ cells are unipotent stem cells that divide to produce gametes in sexually reproducing organisms. A germ cell undergoes meiotic cell division to produce genetically unique, haploid sex cells, which then fuse during fertilization to form a diploid zygote. In female organisms, germ cells give rise to egg cells and, in males, they produce sperm cells.
Germ cells are the cells that give rise to gametes in all sexually reproducing organisms. In vertebrates, they are the precursors of male sperm cells and female egg cells. Collectively, all the germ cells in an organism are known as the germline.
Germ cells are the type of stem cell that gives rise to gametes. They are, therefore, the origin cells of all sexually reproducing organisms, and allow individual members of a species to pass on genetic information to their offspring. The inheritance of DNA is the driving force behind natural selection and evolution, and the fact that germ cells divide by meiosis ensures maximal genetic variation among gametes.
From top paper:
“The spike protein on COVID-19 specifically targets ACE2 and in so doing removes an important stimulus for PI3K/AKT, thereby compromising sperm viability.”
“Alternatively proteases from the TMPRSS-family, either as intrinsic components of the sperm plasma membrane or delivered by seminal prostasomes, can facilitate fusion between the virus and the sperm surface by cleaving ACE2 and the viral spike proteins (S1 and S2) at the sites indicated by dashed lines, thereby completing the transformation of this cell from procreating gamete to viral vector“
Big Pharma Balls? Mutant metaplasia.
“Actual fusion between the virus and human spermatozoa requires the presence of the above-mentioned protease, TMPRSS2, to cleave the viral spike proteins (S) at the S1/S2 boundary or within S2 subunit, thereby removing the structural constraint of S1 on S2 and releasing the internal membrane fusion peptide (Figure 1). This protease is known to be present in prostasomes that are released into seminal fluid from the prostate gland at ejaculation.29 As one of the major functions of these exosome-like structures is to transfer their contents, including proteins, to the spermatozoa following ejaculation, the incorporation of TMPRSS2 from this source seems probable.30 “
How many times must I try to save your nuts?
“The presence of these activating proteases as well as ACE2 in the sperm plasma membrane would be expected to allow the COVID-19 virus to bind to the cell surface and ultimately fuse, either in the testes or during the prolonged sojourn of these cells in the epididymis. In contrast, oocytes appear to be completely devoid of TMPRSS2,33 making infection of the female germ line highly unlikely—unless, of course, they are fertilized by a COVID-19 carrying spermatozoon. In this context, it should be emphasized spermatozoa have a demonstrable capacity to carry viral infections from the male to the female reproductive tract, as happens during the sexual transmission of the Zika virus, for example.34 They also have a proven capacity to fuse with enveloped viruses35 and possess reverse transcriptase activity capable of generating proviral DNA,36 as is apparently the case for human immunodeficiency virus 1.37“
making infection of the female germ line highly unlikely unless, of course, they are fertilized by a COVID-19 carrying spermatozoon
Why did you think they wanted to inject college kids?
We performed this systematic review to evaluate the possibility of an impact of SARS-CoV-2 infection on male fertility. SARS-CoV-2 enters the cells with the help of ACE2; therefore, testicular expression of ACE2 was analysed from transcriptome sequencing studies and our unpublished data. Literature suggested that SARS-CoV-1 (2002-2004 SARS) had a significant adverse impact on testicular architecture, suggesting a high possibility of the impact of SARS-CoV-2 as well. Out of two studies on semen samples from COVID-19 affected patients, one reported the presence of SARS-CoV-2 in the semen samples while the other denied it, raising conflict about its presence in the semen samples and the possibility of sexual transmission. Our transcriptome sequencing studies on rat testicular germ cells showed ACE expression in rat testicular germ cells. We also found ACE2 expression in transcriptome sequencing data for human spermatozoa, corroborating its presence in the testicular germ cells. Transcriptome sequencing data from literature search revealed ACE2 expression in the germ, Sertoli and Leydig cells. The presence of ACE2 on almost all testicular cells and the report of a significant impact of previous SARS coronavirus on testes suggest that SARS-CoV-2 is highly likely to affect testicular tissue, semen parameters and male fertility.
Several studies have demonstrated the presence of viral RNA in the feces of patients affected by COVID-19, suggesting the possibility of viral transmission through the oral–fecal route (Nouri‐Vaskeh & Alizadeh, 2020; Zhang et al., 2020). Furthermore, there is evidence proving that fecal tests continue to be positive even after the respiratory specimens become negative (Tian, Rong, Nian, & He, 2020).
Studies aimed at investigating the potential mechanisms underlying SARS-CoV-2 transmission and infection at the level of the oral cavity have shown that ACE2 is expressed by the mucosal epithelial cells. The expression of this molecule is higher at the tongue level than in gingival and buccal tissues, indicating it as a possible route of infection (Xu et al., 2020). Moreover, live viruses were detected in the saliva of infected individuals (To et al., 2020).
In order to explore the possibility of sexual transmission, the presence of SARS-CoV-2 was tested in vaginal fluid and semen of SARS-CoV-2-positive patients. In one study (Pan et al., 2020), Sars-CoV-2 was detected in semen samples of 34 Chinese men recovering from COVID-19 with milder symptoms. In two other studies, one in which 35 female COVID-19 patients were recruited and who came from different geographical areas of Wuhan (Cui et al., 2020) and another in which were 10 postmenopausal woman with severe COVID-19 were recruited (Qiu et al., 2020), Sars-CoV-2 was detected in vaginal fluids. In these studies, SARS-CoV-2 was not found either in semen or in vaginal fluids of positive cases.
This does not exclude the possibility of viral transmission through sexual behavior (e.g., oral/anal contacts). Indeed, viral particles may be transmitted through oral sex and use of saliva as a lubricant. This is supported, as previously described, by the shedding of viral particles through the saliva and the feces and the presence of ACE2 receptors on the epithelium lining the oral cavity and the rectum.
…Shut down Tinder.
Physicians should inform their patients about these risk behaviors in order to avoid further spreading of the virus. The importance of increasing awareness on less common transmission routes stems from the high number of contagious persons, including asymptomatic individuals and patients with double–negative oro/nasopharyngeal swab, but still potentially contagious (persistent fecal elimination of the virus).