Endometrial susceptibility to SARS CoV-2: explained by gene expression across the menstrual cycle?

Abstract

On March 11, 2020, the World Health Organization declared the outbreak of severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) a global pandemic, reporting community-scale transmission worldwide with more than 8 million cases of confirmed coronavirus disease (COVID-19). On March 17, the American Society for Reproductive Medicine provided early key recommendations, updated and affirmed on March 30, including suspending initiation of new treatment cycles aimed at achieving pregnancy. The European Society of Human Reproduction and Embryology provided similar recommendations that expanded even further to include consideration of avoidance of spontaneous conception. These recommendations were made in the infancy of the pandemic when little was known about the implications of the novel coronavirus on implantation and pregnancy. Over the past several months, new developments in molecular virology and immunobiology of SARS-CoV-2 have improved our understanding of the novel coronavirus. In light of the rapidly expanding knowledge base and the realization that care cannot be paused indefinitely, fertility clinics around the world are beginning to resume treatment.As fertility care recommences, the potential impact of SARS-CoV-2 on implantation and early pregnancy is increasingly relevant. Understanding the pathophysiology of the virus and the target tissues at a molecular level can help clarify the potential short-and long-term implications of infection on implantation, miscarriage, the intrauterine milieu, the placenta, and pregnancy and neonatal outcomes (1).The genome sequence of SARS-CoV-2 is similar to, but distinct from the two other coronaviruses, as it has about 80% sequence identity with SARS-CoV and about 50% with MERS-Cov-2. Similar to SARS-CoV, the spike (S) protein of SARS-CoV-2 facilitates viral entry into target cells. Entry depends on binding of the S1 subunit of the S protein to a cellular receptor. Multiple studies have also confirmed that SARS-CoV-2 engages angiotensin-converting enzyme 2 (ACE2) as the entry receptor. In addition, viral entry depends on priming cleavage of the S protein, between S1 and S2, and activating cleavage on the S2ʹ site. Depending on virus strains and cell types, proteins may be cleaved by one or several host proteases, including furin, trypsin, cathepsins, transmembrane protease serine protease-2 (TMPRSS2), or TMPRSS4 (2-4).To date, the impact of SARS-CoV-2 on endometrial lining and implantation remains largely unknown, so the study by Henarejos-Castillo et al. ( 5) is of utmost importance. The authors assessed endometrial susceptibility to SARS-CoV-2 infection by measuring endometrial ACE2, TMPRSS2, TMPRSS4, cathepsin B and L (CTSB and CTSL, respectively), FURIN, MX dynamin-like GTPase 1 (MX1), and Basigin (BSG) gene expression. The group used public transcriptomic data sets to evaluate the risk of endometrial SARS-CoV-2 infec-

Effect of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on reproductive system

“…This finding suggested that the liver admages of SARS-CoV and SARS-CoV-2 patients may be result in cholangiocyte dysfunction and another causes like drug induced and systemic inflammatory response induced liver injury ( Chai et al, 2020 ). Importantly, there are several studies confirmed that ACE2 expression profile both in male and female reproductive systems ( Abhari and Kawwass, 2020 , Fan et al, 2020 , Verdecchia et al, 2020 , Yan et al, 2020 ) ( Fig. 4 ).…”

“…The expression of ACE2 was low. TMPRSS4 was expressed in all menstrual cycles, especially during menstruation, which cleaves S protein and enables SARS-CoV-2 to bind to ACE2, to infect cells, even if the expression of ACE2 was low ( Abhari and Kawwass, 2020 , Henarejos-Castillo et al, 2020 ). Especially, Diaz-Gimeno’s study also found that from the proliferative phase to the middle secretory stage of the endometrium, especially in the early secretory stage, there was a positive correlation between age and ACE2, which mean that older women may be more likely to be infected with SARS-CoV-2 ( Henarejos-Castillo et al, 2020 ) ( Fig.…”

Does Endometriosis Increase Susceptibility to COVID–19 Infections? A case-control study in Women of Reproductive Age

“…It is also assumed that COVID-19 can induce changes in endometrial tissue and affect the female reproductive potential (26). However, the susceptibility of endometrial tissue to COVID-19 has not been con rmed in the clinical setting (14). Studying large databases has shown that the uterine corpus endometrial carcinoma tissue is more susceptible to SARS-CoV-2 infection, which also affected the tumor prognosis after COVID-19 infection (27).…”

“…Previous studies on the endometrial disease have also determined the presence of ACE 2 in the glandular epithelium, stroma, perivascular space, and endothelium, and its signi cant increase in endometrial cancer tissue (12,13). Therefore, clinical studies are required to determine the risk of COVID-19 infection in the endometrial tissue (14).…”

Potential effects of COVID-19 on reproductive systems and fertility; assisted reproductive technology guidelines and considerations: a review

“…They also reported a positive correlation between age and SARS-CoV-2-related gene expression (ACE2), suggesting increased susceptibility to endometrial infection in older women. 14,15 A normal level of Ang II expression is crucial to maintaining regular menstrual cycles and endometrial activity, as it facilitates regeneration of blood vessels and the endometrium and initiates menstruation. 8 Endometrial and myometrial activities including endometrial regeneration, proliferation, fibrosis, and stromal proliferation are regulated by the intricate balance of Ang II and Ang-(1-7) in the uterus, ie, stimulated by Ang II and inhibited by Ang-(1-7).…”