ACE2 Receptor and Its Isoform Short-ACE2 Are Expressed on Human Spermatozoa

Ramal-Sanchez, Marina; Castellini, Chiara; Cimini, Costanza; Taraschi, Angela; Valbonetti, Luca; Barbonetti, Arcangelo; Bernabò, Nicola; Barboni, Barbara

doi:10.3390/ijms23073694

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…Through scRNA-seq datasets analysis, ACE2 expression, but no co-expression of ACE2 and TMPRSS2, was reported in sperm ( Stanley et al , 2020 ), and BSG/CSTL co-expression was reported in early and late primary spermatocytes ( Stanley et al , 2020 ). The ACE2 protein is expressed on mature spermatozoa after ejaculation, as documented from western blot analysis ( Ramal-Sanchez et al , 2022 ).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2, fertility and assisted reproduction

Ata

Vermeulen

Mocanu

et al. 2022

Human Reproduction Update

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BACKGROUND In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain. OBJECTIVE AND RATIONALE This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals. SEARCH METHODS PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on ‘SARS-CoV-2’ and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible. OUTCOMES From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients’ performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients. WIDER IMPLICATIONS This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2, fertility and assisted reproduction

Ata

Vermeulen

Mocanu

et al. 2022

Human Reproduction Update

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“…If IgA and IgG recognize the SARS-CoV-2 receptor Angiotensin-converting enzyme-2, this can explain the attachment of IgA/IgG-ASA to the tail of spermatozoa, because the receptor is also located on the sperm tail. 26 , 27 Conversely, harmful sIgG-N in blood only significantly correlated with higher DFI. Similarly, early in the pandemic it became clear that our immune system can produce antibodies that are protective or harmful.…”

Section: Discussionmentioning

confidence: 91%

SARS-CoV-2 infection reduces quality of sperm parameters: prospective one year follow-up study in 93 patients

Depuydt¹,

Bosmans²,

Jonckheere³

et al. 2023

eBioMedicine

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“…This specific viral route of entry we demonstrated with our study lets us hypothesize a possible mechanism by which SARS-CoV-2 may affect spermatogenesis; indeed, Leydig cell damage is associated with disrupted spermatogenesis [ 35 ]. The ACE2 receptor and its short isoform were recently shown to be expressed in human spermatozoa [ 36 ]. In this study, we not only confirmed this data but also analysed the expression of the specific host proteases TMPRSS2, CSTL, and BSG, known to be involved in the cleavage of the S protein, which activates ACE2-mediated virus entry.…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Mechanisms of In Vivo and In Vitro SARS-CoV-2 Infection: A Lesson from Human Sperm

Luddi

Luongo

Dragoni

et al. 2022

Cells

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Despite the major target of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, being the respiratory system, clinical evidence suggests that the male reproductive system may represent another viral target organ. Revealing the effect of SARS-CoV-2 infection on testis and sperm is a priority for reproductive biology, as well as for reproductive medicine. Here, we confirmed that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on human testis and ejaculated sperm; moreover, we provide evidence for the expression of the co-receptors transmembrane protease/serine (TMPRSS2), Basigin (BSG), and Catepsin L (CTSL). Human sperm were readily infected, both in vivo and in vitro, by SARS-CoV-2, as demonstrated by confocal and electron microscopy. The demonstration that the seminiferous epithelium and sperm support SARS-CoV-2 viral replication suggests the possibility that the spermatogenetic process may be detrimentally affected by the virus, and at the same time, supports the need to implement safety measures and guidelines to ensure specific care in reproductive medicine.

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ACE2 Receptor and Its Isoform Short-ACE2 Are Expressed on Human Spermatozoa

Cited by 8 publications

References 36 publications

SARS-CoV-2, fertility and assisted reproduction

SARS-CoV-2, fertility and assisted reproduction

SARS-CoV-2 infection reduces quality of sperm parameters: prospective one year follow-up study in 93 patients

Cellular and Molecular Mechanisms of In Vivo and In Vitro SARS-CoV-2 Infection: A Lesson from Human Sperm

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