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Can molecular mimicry impact fertility in female COVID-19 patients?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). SARS-CoV-2 is well known to cause severe respiratory illness in infected patients. However, studies have found that it can affect multiple organs like the heart and brain as well. Some people who have recovered from COVID-19 have been found to develop multisystem inflammatory syndrome leading to inflamed organs and tissues. The impact of COVID-19 on various systems in the body can manifest as long-term side effects. There exists a possibility that COVID-19 can also affect the reproductive function in the body, which can lead to infertility in infected patients. A study published in the American Journal of Reproductive Immunology explored the impact of SARS-CoV-2 infection on reproductive functions and fertility.

How can COVID-19 infection impact fertility?

The scientists have propounded three ways that SARS-CoV-2 infection can influence the reproductive system and impact fertility:

Direct action of SARS-CoV-2 on Angiotensin-converting enzyme -2 (ACE2) receptor may impact fertility

Angiotensin-converting enzyme -2 (ACE2) receptor plays a vital role in various physiological processes. It is present in the kidneys, heart, thyroid, adipose tissue, and the reproductive system (testis, ovaries, uterus, vagina, and placenta). ACE2 has been found to play a role in follicular development, ovulation, luteal degeneration, endometrial changes, embryo development, etc. Recent evidence suggests that ACE2 also has a vital role in SARS-CoV-2 pathogenesis by facilitating viral entry into host cells. It has been hypothesized that SARS-CoV-2 may act through the ACE2 receptors on the reproductive system and disrupt its functioning.

Evasion of autophagy in the host cell by SARS-CoV-2 may disrupt oocyte maturity

An important mechanism of SARS-CoV-2 pathogenesis is the evasion of the autophagic system in the host cell. Autophagy is a self-cleaning process by which a cell removes unwanted debris, malformed proteins, damaged organelles, etc. Both autophagy and oxidative stress have a role in oocyte longevity. Therefore, by disrupting autophagy in host cells, SARS-CoV-2 may impact oocyte maturation and fertility.

Molecular mimicry between the host and SARS-CoV-2 proteins may influence fertility

The amino acid sequences in the proteins of the host cells and SARS-CoV-2 may exhibit similarities. This can result in cross-reactivity of the antibodies produced by the infected patients against SARS-CoV-2, leading to an autoimmune state where their cells are harmed. This condition is called molecular mimicry.  In earlier studies, it was observed that molecular mimicry between hepatitis B virus (HBV) proteins and myelin basic protein in mice leads to the onset of demyelinating diseases after HBV infection. Molecular mimicry between SARS-CoV-2 proteins and oogenesis-associated proteins may affect reproductive function.

The scientists in this study explored if molecular mimicry affects fertility in COVID-19 infected patients

The hypothesis of this study is SARS-CoV-2 proteins share common peptide sequences with the proteins involved in oogenesis resulting in the production of cross-reactive antibodies. These cross-reactive antibodies may result in the onset of autoimmune diseases.

Peptide sequences made of 5 amino acids (pentapeptides) are considered a minimum requirement for inducing peptide-specific antibodies and for provoking antigen and antibody reactions. Pentapeptides were used as peptide probes for identifying similarities between human oogenesis-associated proteins and spike protein from SARS-CoV-2.

The UniProtKB database was used to identify eighty-two human oogenesis-associated proteins. These proteins were joined to artificially create a polyprotein. Further, the spike protein from SARS-CoV-2 was divided into pentapeptides. Analysis was performed to assess if the pentapeptides from the spike protein occurred in the polyprotein. If common pentapeptides were identified, they were checked for their immunoreactivity on the Immune Epitope Database.

What did the scientists find?

Peptides that occurred in both the human oogenesis-related protein and the SARS-CoV-2 spike protein are immunoreactive. It was found from the analysis that forty-one pentapeptides from SARS-CoV-2 spike protein occurred in twenty-seven human oogenesis-associated proteins. On the Immune Epitope Database, it was found that all of the matching pentapeptides except for two have been identified to be immunoreactive.

COVID-19 patients may develop an autoimmune condition that can affect their fertility

  • There exist amino acid sequence similarities between human oogenesis-associated proteins and SARS-CoV-2 spike protein which can elicit the production of cross-reactive antibodies.
  • In the present study, it was found that during SARS-CoV-2 infection, there is a possibility of cross-reactive antibodies being produced against various proteins associated with the reproductive system. This can affect fertility and cause disruptions in the reproductive function of the infected patient.  
  • Some of the possible effects of cross-reactive antibodies attacking the human oogenesis-related proteins include; destruction of germ cells, reduction in the size of the testis and ovaries, alterations in the expression of genes associated with sexual dimorphism, aberrations in the reproductive function, lack of sexual maturation, etc.

The results from the present study are preliminary and indicate a possibility that COVID-19 infected patients may develop an autoimmune condition that can affect their fertility. A more in-depth investigation is required to confirm the findings from this study. Further, the presence of autoantibodies against proteins associated with the reproductive system should be assessed in COVID-19 patients.

Sources:

Journal reference:

  • Dotan, A., Kanduc, D., Muller, S., Makatsariya, A. and Shoenfeld, Y. (2021), Molecular mimicry between SARS-CoV-2 and the female reproductive system. Am J Reprod Immunol. Accepted Author Manuscript. https://doi.org/10.1111/aji.13494
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