Studying the disparate immune responses of men and women to the COVID-19

Scientists unravel the mystery of sex disparities in COVID-19 outcomes.


The age-related changes in various immunological parameters are different between men and women. Recently, it was discovered that the gene expression pattern that controls innate immune responses to viral infections begins to decrease dramatically in men between the ages of 62 and 64. In women, this immune response begins to wane about six years later in life.

In a new study, Yale immunobiologist Akiko Iwasaki studied the disparate immune responses of men and women to COVID-19. In particular, she studied how age affects these responses.

She hopes that the study could uncover the hidden mechanism of this mysterious new pathogen.

By April 2020, Iwasaki’s lab had completed research detailing the specific molecular differences in the immune system response of men and women. They were able to identify the molecules that offer protection against viruses. They also identified the molecules associated with poorer outcomes.

Over the last year, Iwasaki and her colleagues worldwide have compiled a rich literature of research that reveals in detail these and other factors that make the virus more lethal for men.

They found that men are 1.7 times more likely to die from the virus than women. What is the reason behind this?

Scientists noted, “One of the first explanations comes from basic biology. Women have two X chromosomes, whereas men have one. X chromosomes are enriched in genes that regulate immune response; hence they are important.”

“While one of those X chromosomes in women is silenced, in some cases key genes from both X chromosomes can activate the innate immune system, the early alarm system that detects pathogens. Essentially, women have immune system reinforcements they can call upon early in infections than men, with their single X chromosomes, don’t possess.”

According to a study, sex hormones have a significant role in susceptibility to bad outcomes. In a mouse model of SARS-CoV infection, higher mortality in male mice was observed and attributed to the female sex hormone estrogen’s protective roles. The presence of estrogen can help suppress ACE 2, an entry receptor for SARS-CoV-2. Conversely, the male hormone androgen appears to enhance the ability of the virus to infect cells.

Likewise, age amplifies and some of the time disrupts a man’s immune response to COVID-19 infection. As men in their early 60s start to lose their capacity to mount an initial immune response to the novel Coronavirus, frequently there is additionally a compensatory overreaction by other immune system molecules that can prompt damaging inflammation. These inflammatory factors can trigger the so-called “cytokine storm,” which can cause damage to the lungs and other tissue, which is a hallmark of severe COVID-19 cases.

Iwasaki said, “Uncovering the details of differing immune system responses of men and women will inform both vaccine development and better clinical treatments. 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.”

Journal Reference:

  1. Takehiro Takahashi et al. Sex differences in immune responses. DOI: 10.1126/science.abe7199
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