By Priyadarshini Chatterjee

As the SARS-CoV-2, or more commonly known as Covid-19, pandemic continues to spread, epidemiologists seem to be churning out some mind-boggling numbers. Recently, I came across a puzzling statistic which concluded that women were less likely to die from contracting Covid-19 than men were. Additionally, this was in the above 65 years category, where there is a higher percentage of women than men. Delving into the literature, looking for an explanation to make sense of the difference in death rate, I found an extremely neat explanation relating to X chromosome inactivation.

Men and women are biologically distinct; males have an X and a Y chromosome (XY), while females have two X chromosomes (XX). Each sex chromosome comes from either parent and the X and the Y chromosome each express a different set of genes. This means that females express two sets of X chromosome genes while males express just one. To ensure balance and equal dosage of the X chromosome, random, stochastic inactivation of one of the two X chromosomes occur during embryonic development in females. This gives rise to a mosaic expression pattern, where either the maternal or the paternal X chromosome is expressed.

But what does this have to do with SARS-CoV-2 immunity?

A large number of immune genes are located on the X chromosome and as most, if not all, biological processes are not 100% efficient and have a certain degree of “leakiness”, X chromosome inactivation can be skewed and certain genes can even escape X chromosome inactivation. This would explain why females have more active immune-related genes; in particular, females show greater cell-mediated responses and antibody production. This would account for the patient data showing that men have fewer B cells than women and would explain why women clear the virus faster than men.

The phenomenon of a “cytokine storm”, that is characteristic of the virus, seems to be occurring more frequently in men than in women. A cytokine storm is the excess production of inflammatory molecules and chemicals in the body, causing the immune system to become hyperactive and go into overdrive. Women are thought to be protected against it due to the random inactivation of such genes on one of their X chromosomes. The mosaic patterning can fine tune the release of such inflammatory molecules that contribute to the cytokine storm.

Similarly, the infamous ACE2 receptor gene, by which the virus enters cells, is also located on the X chromosome. The resultant heterozygous express in females as well as the fact that the ACE2 gene has a different “molecular fingerprint”, known as a single nucleotide polymorphism (SNP) in females and males, allows the ACE2 receptor to bind to the virus with different affinities.

While the virus does not discriminate while infecting, there does seem to be an innate biological difference in recovering from the virus, which explains the recovery rates seen. The specifics of X chromosome inactivation are yet to be unravelled and this area, specifically in the context of infectious disease, is still under active research.

Further Reading

Gemmati, D., Bramanti, B., Luisa Serino, M. Secchiero, P., Zauli, G., Tisato, V. (2020). COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? International Journal of Molecular Sciences. https://www.mdpi.com/1422-0067/21/10/3474/htm

Marquesz, E.J., Trowbridge, J., Kuchel, G.A., Banchereau, J., Ucar, D. (2020). The lethal sex gap: COVID-19. Europe PMC. https://europepmc.org/article/PMC/PMC7240166#Sec2

Schurz, H., Salie, M., Tromp, G., Hoal, E.G., Kinnear, C.J., Moller, M. (2019) The X Chromosome and Sex-Specific Effects in Infectious Disease Susceptibility. Human Genomics. https://humgenomics.biomedcentral.com/articles/10.1186/s40246-018-0185-z

Priyadarshini Chatterjee is a third-year Biochemist at the University of Oxford. She is extremely interested in infectious diseases, in particular, those caused by viruses. She is passionate about scientific outreach and communication. In her spare time, she enjoys reading and playing the piano.