In the last year, it has become painfully apparent that the new coronavirus, SARS-CoV-2, while initially targeting the respiratory system, can affect several tissues and organs and result in a plethora of symptoms and sequelae. Although the scientific literature on the coronavirus abounds, the effects of a SARS-CoV-2 infection on our reproductive function are still poorly understood. From the point of view of developing guidelines for the safe provision of assisted reproduction technology (ART) treatments during the current COVID-19 pandemic, a central concern is the possibility of vertical transmission of SARS-CoV-2 infection through gametes.
In other words, can the virus infect human oocytes and sperm? Can the use of oocytes from women infected with the virus result in an infection of the developing embryo?
For the virus to infect a cell, it must find two elements on the cell's surface membrane: a receptor which will anchor the virus, and a protease which will facilitate its entry into the cell. We have all become accustomed to the names of ACE2, the protein that acts as a receptor for the virus, and TMPRSS2, the protease which helps initiate the infection of the cell. Additionally, it has also been reported that the BSG receptor and the CTSL protease can also be used by the virus.
The mRNAs of these genes are expressed in most of the human female reproductive tract, and during the early developmental stages of the human embryo. Normally, the presence of mRNA, the precursor molecule needed to produce the protein, may be used as an indication of concomitant protein production. However, this general association is not absolute, especially in cells, like the oocyte, designed to store mRNAs for a long time before making the corresponding protein at exactly the time when it is needed. Reports on the presence of ACE2 and TMPRSS2 proteins in oocytes, rather than mRNAs, are extremely scarce, as are data from women with a confirmed SARS-CoV-2 infection.
We identified an opportunity to bridge this gap in knowledge when, in early March 2019, we identified two young oocyte donors who, despite the absence of symptoms, were positive for SARS-CoV-2 infection on the day of the oocytes collection. Their oocytes were frozen pending further assessment, and, with their consent, 16 oocytes were tested individually for presence of viral material. None of the 16 measurements returned a positive result, meaning no viral material was identified in any of the oocytes.
Regardless of the detection of viral material in oocytes, one wonders about the possibility for the virus to infect them, perhaps when present in higher concentration in the reproductive organs, or in women presenting symptoms and a more severe form of COVID-19. To that extent, we have analysed the presence of both mRNAs and protein for the four genes related to SARS-CoV-2 infection initiation: ACE2 and TMPRSS2 on the one hand, and BSG and CTSL on the other. We found that ACE2 mRNA was present in some of the oocytes, while TMPRSS2 was undetectable in our cohort. Moreover, we did find some expression of the BSG and CTSL mRNAs in these oocytes. Fortunately, when we moved on to assess the presence on the four proteins, we found that only BSG is clearly present on the cellular surface of the human oocyte, while the other proteins cannot be detected.
Taken together, our results indicate that the likelihood for human oocytes to become infected with SARS-CoV-2 is very low, as they seem to lack the biochemical machinery to allow for virus entry, or they have it but at undetectable level.
What does this mean for the provision of ART services? Most likely, finding oneself positive after oocyte collection, perhaps through contact tracing, would not mean an increased risk for the oocyte or the deriving embryos.
Can we then suspend SARS-CoV-2 testing in ART patients? No, we should not, it is important to not start an IVF cycle, or any medical treatment that can be reasonably postponed, if the patient is currently infected with SARS-CoV-2. The important point in this case is to avoid unnecessary risks of complications to the patient, and of infection to the healthcare workers attending them.
Overall, the possibility of transmitting the virus to a woman's oocytes seem very small, and this should give some level of comfort to the thousands of patients facing ART treatment in these times of great uncertainty.