It is hard to understand why being a man is such a strong risk factor for dying from COVID-19.
Now, though, Yale researchers have revealed biological mechanisms that make men more vulnerable than women to SARS-CoV-2.
Their research has revealed that the immune response is affected by aging depending on sex, which in turn influences the incidence and severity of COVID-19.
The differences in genetic makeup and sex hormones may account for the doubling of the COVID mortality risk in men.
The female sex hormone estrogen reduces the ability of the virus to infect cells and the two X chromosomes keep the immune system alert to detect pathogens.
This basic biology provides a higher protection for women.
Professor Akiko Iwasaki, the study’s first author, said:
“Age and sex are where immunological changes intersect.”
Recent studies show that gene expression regulates our immune response and tells the immune cells how to react to a threat.
Immunity weakens with age, but due to lower gene expression related to adaptive immunity the decline is much faster in men.
The changes in immune system in men occur dramatically between ages 62 and 64 whereas the decline in immune responses starts in women six years later than that.
Iwasaki’s lab has identified certain molecules that improve immune response against COVID-19 and those causing adverse effects on health.
The research explains why the risk of death for the virus is 1.7 times higher in men than women.
It seems that X chromosomes contain genes that control the immune responses.
Women have two X chromosomes which is an advantage here.
In women, when one X chromosome is silenced the other chromosome is still active meaning the immune system will get more effective against an infection than in men with their single X chromosome.
Also, the male sex hormone androgen appears to be an important factor associated with worse outcomes, while the female sex hormone estrogen provides protection in woman with COVID-19.
Estrogen suppresses ACE 2 receptors which are the entry point for SARS-CoV-2 to infect cells.
On the other hand, androgen increases the virus’ ability to infect cells.
Age is another risk factor disrupting immune responses in men against the coronavirus.
Males in their early 60s lack the ability to create an initial immune response against the virus so other immune system molecules overreact to compensate for this issue.
This may lead to cytokine storm, a life-threatening inflammatory syndrome which can lead to lung failure in some COVID-19 patients.
Professor Iwasaki concluded:
“I knew we would learn a lot about immunity to this virus by studying sex differences, but I didn’t know the findings would be this clear.
Hopefully, vaccines will start to level the playing field between men and women and reduce deaths for everyone.”
The study was published in the journal Science (Takahashi & Iwasaki, 2021).