Female reproductive organs not susceptible to direct SARS-CoV-2 infection

Researchers at the University in San Francisco, California, report that coronavirus disease 2019 (COVID-19) is unlikely to negatively impact on pregnancy-related outcomes such as premature birth, transmission to babies via breast milk, and infertility.

During the COVID-19 pandemic, concerns have arisen about the potential impacts of the disease on reproductive outcomes. A limited number of studies have suggested that the causative agent – severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – may cause miscarriages, premature birth, stillbirth, and restricted fetal growth due to placental abnormalities.

However, Aleksandar Rajkovic and colleagues found that none of the reproductive tissues they studied seemed to be susceptible to infection with SARS-CoV-2.

None of the cells in the uterus, myometrium (uterine smooth muscle), ovary, fallopian tube, and breast expressed the combination of receptors ad proteases that would be needed to facilitate viral entry.

The authors say this may explain why the COVID-19 pandemic seems to have had little impact on the incidence of pregnancy complications and infertility.

A pre-print version of the paper is available on the server bioRxiv*, while the article undergoes peer review.

SARS-CoV-2 viruses binding to ACE-2 receptors on a human cell, the initial stage of COVID-19 infection. Illustration credit: Kateryna Kon / Shutterstock
SARS-CoV-2 viruses binding to ACE-2 receptors on a human cell, the initial stage of COVID-19 infection. Illustration credit: Kateryna Kon / Shutterstock

How does SARS-CoV-2 infect cells?

Since the COVID-19 outbreak first began in Wuhan, China, late last year, SARS-CoV-2 has infected more than 9.16 million people globally and caused more than 473,000 deaths.

SARS-CoV-2 binds to the host cell receptor ACE2 using the Spike protein on its surface, which is then primed by transmembrane protease serine 2 (TMPRSS2) to mediate viral entry.

Alternatively, in the absence of TMPRSS2, the virus can use the proteases cathepsin B (CTSB) and cathepsin L (CTSL) to enter host cells.

Recent studies of single-cell sequencing datasets have shown increased expression of ACE2 and TMPRSS2 in the nasal epithelium and lung. They have also shown susceptibility to SARS-CoV-2 in cells other than the respiratory tract, including the heart, colon, and cornea, which may account for symptoms such as cardiovascular inflammation, diarrhea, and conjunctivitis.

Concerns about the impact on pregnancy outcomes

Given that SARS-CoV-2 can infect multiple organs, significant concerns have arisen regarding the impact that infected reproductive organs may have on pregnancy- and fertility-related outcomes.

A limited number of studies have suggested the virus can cause miscarriage, premature birth, stillbirth, and restricted fetal growth owing to placental abnormalities.

However, these studies have been small and generated conflicting data, meaning the likelihood of SARS-CoV-2 affecting pregnancy and transmission to the neonate is still unclear.

Now, Rajkovic and colleagues have investigated the cell-specific expression of ACE2 and the proteases TMPRSS2, CTSB, and CTSL in female reproductive organs. The team used single-cell RNA sequencing datasets from the uterus, myometrium, ovary, fallopian tube, and breast.

“Our study gave us critical insights into the expression of SARS-CoV2 receptor and proteases TMPRSS2, CTSB/L in the female reproductive tract,” writes the team.

Findings in the uterus and myometrium

The team identified very low expression of ACE2 in stromal and endothelial cells of the uterus.

However, ACE2 was not co-expressed with any of the proteases implicated in viral host cell entry, leading the researchers to conclude, “it seems unlikely that the uterus will be affected by COVID-19.”

In the myometrium, which controls uterine contractions and plays a crucial role in labor onset, no co-expression of ACE2 with TMPRSS2, CTSB, or CTSL was identified, suggesting that tissue is also unlikely to be affected, say the researchers.

“SARS-CoV-2 is therefore unlikely to directly contribute to abnormal uterine function which may result in implantation failure, preterm birth, and early placentation,” writes the team.

Findings in the ovary and fallopian tube

Across eight types of ovarian cells, although ACE2 was expressed in about one percent of stromal and perivascular cells, TMPRSS2 was not expressed in any cell type.

In addition, very few cells in the fallopian tube expressed ACE2 and none co-expressed ACE2 and TMPRSS2.

Overall, the team did not find any cells co-expressing ACE2 and TMPRSS2 or CTSB/L in either the ovary or the fallopian tube.

“Together, these results suggest that SARS-CoV2 is unlikely to affect female fertility,” say the researchers.

What about the breast?

“Current obstetric protocols for infected mothers in labor, call for temporary separation of mother and baby to prevent SARS-CoV2 transmission,” say Rajkovic and colleagues.

On analyzing the dataset for breast epithelium, the researchers found low expression of ACE2 in luminal epithelium and myofibroblasts. Still, no ACE2 was co-expressed with TMPRSS2 or CTSB/L in any of the cell types.

“These findings suggest that the virus might not be able to penetrate the mammary gland cells. Therefore, the chances of transmission of the virus through breastfeeding are negligible,” writes the team.

“COVID-19 is unlikely to contribute to pregnancy-related adverse outcomes”

The researchers say the results suggest that none of the reproductive tissues investigated in this study are likely to be susceptible to SARS-CoV-2 infection.

“Our findings suggest that COVID-19 is unlikely to contribute to pregnancy-related adverse outcomes such as preterm birth, the transmission of COVID-19 through breast milk, and female infertility,” they write.

“These data may explain the low incidence of complications among pregnant women and little evidence for higher infertility,” concludes the team.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally has a Bachelor's Degree in Biomedical Sciences (B.Sc.). She is a specialist in reviewing and summarising the latest findings across all areas of medicine covered in major, high-impact, world-leading international medical journals, international press conferences and bulletins from governmental agencies and regulatory bodies. At News-Medical, Sally generates daily news features, life science articles and interview coverage.

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