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?:abstract
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Objective: To identify cell types in male and female reproductive systems at risk of SARS-CoV-2 infection based on expression of viral host entry proteins Design: Transcriptomic and proteomic analysis Materials and Methods: Publicly available single cell RNA sequencing (scRNAseq) data in human testis and non-human primate ovary was analyzed, as well as bulk RNA and proteomic data in human testis and ovary Additionally, novel RNA sequencing data from 18 samples of human cumulus cells was generated Tissue- and cell-type specific risk of viral infection was predicted based on the co-expression of host receptor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) which are required for viral binding and cleavage, respectively Expression of receptor basigin (BSG) and cysteine protease cathepsins L (CTSL) were also assessed as they are hypothesized to facilitate viral entry Results: Based on scRNAseq data in non-human primate ovarian tissue, ACE2 and TMPRSS2 co-localize in a sub-population of oocytes in antral follicles (62% of cells, Pearson correlation=0 37), but to a lesser extent in less mature oocytes (Pearson correlation=0 13- 21) and not at all in ovarian somatic cells While ACE2 transcripts were detected in human cumulus cells (mean 24 03 transcripts per million), TMPRSS2 expression was absent in 15/18 samples and low in the others (0 13 TPM) Consistent with these findings, bulk RNA and protein data showed ACE2 expression in ovarian tissue, but no TMPRSS2 expression In testicular cells, including sperm, co-expression of ACE2 and TMPRSS2 was not detected (Pearson correlation=-0 01) Bulk RNA and protein data revealed ACE2 but no TMPRSS2 expression BSG was more broadly expressed in testis than ACE2 and was co-expressed with CSTL in early (78 7%) and late (90 8%) primary spermatocytes Conclusions: Given that known COVID-19 symptoms are associated with tissues co-expressing ACE2 and TMPRSS2 (e g lung, heart, kidney, gut), it is conceivable that reproductive function could be effected if constituent cells co-express these genes Based on these results, testicular cells including sperm are not at risk of ACE2-TMPRSS2-mediated viral entry, however low levels of SARS-Cov-2 in human semen have been reported and may suggest alternative routes of entry The cells predicted to have the greatest susceptibility to infection are antral oocytes which are either ovulated or atrophy within several days of appearance each cycle and are therefore unlikely to have sustained impact on female fertility if infected Moreover, the lack of ACE2-TMPRSS2 expression in cumulus cells may act as a barrier to infection Therefore, procedures in which cumulus cell-enclosed oocytes are collected and fertilized outside the female reproductive tract (e g IVF) may not pose a risk IVF success rates decline with increasing female age and it is therefore imperative that patients are allowed to access fertility treatments if safe to do so The results presented here are indicative, but ovarian pathology data from women of reproductive age with COVID-19 at time of death is needed for definitive confirmation
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