Why do fewer women die of COVID? The answer could lie in the X chromosome’s superpower

It’s a mystery that has left doctors scratching their heads for decades: Why, compared to women, are men more likely to get sick and even die from viral infections?

Take SARS-CoV-2, for example. According to the National Institutes of Health (NIH), males made up a majority of COVID-19 deaths. In fact, males were three times more likely to be admitted to the intensive care unit and had a 15 percent higher chance of dying than females.

It isn’t just COVID-19 either. When the Middle East Respiratory Syndrome (MERS) outbreak occurred in 2014, 32 percent of infected men died compared to 26 percent of women. During the 1918 influenza pandemic, young adult men died at higher rates compared to females.

“We find that a lot of males tend to be more susceptible to viral infections, and one major example that we’ve seen is with SARS-CoV-2,” Cheng said. “And our big question is, ‘Why?'”

Indeed, scientists have long wondered why some viruses affect males more than females. Could it be a difference in immune systems, sex hormones, environmental factors — or something else?

According to a new study published in the peer-reviewed journal Nature Immunology, the answer could simply lie in a chromosomal difference. In those without chromosomal abnormalities, males have XY chromosomes, females have XX. Could there be something more protective about having the extra X chromosome?

Mandy Cheng, PhD, lead author and a postdoctoral student in molecular biology at University of California, Los Angeles, told Salon she and her colleagues were interested in understanding the main immune responsive differences between males and females.

“We find that a lot of males tend to be more susceptible to viral infections, and one major example that we’ve seen is with SARS-CoV-2,” Cheng said. “And our big question is, ‘Why?'”

Cheng and her colleagues looked at NK cells, which males typically have more of than females. NK cells are a type of white blood cell that kills human cells that are infected with a virus. While males have more of these cells, it was confusing to scientists as to why having a higher number of them didn’t necessarily equate to a higher level of protection.

Additionally, there was little knowledge as to whether there were sexual differences to NK cells, aside from the number.

In lab work, Cheng and her colleagues found that both female mice and human females’ NK cells have an extra copy of UTX, a gene specifically associated with the X chromosome. UTX acts as an epigenetic regulator, which boosts NK cells’ function when it comes to fighting viruses.

“Under the same inflammatory conditions, it seems like females make a lot more immune mediator[s] — such as interferon gamma, which is what we mentioned in the study,” Cheng said. Interferon gamma, Chen noted, is a “super important molecule” that helps damage viruses and virally-infected cells. 

Because the gene that controls the expression of interferon gamma is on the X chromosome, it “escapes X inactivation in females” — meaning “there’s more of it in females compared to males.”

Cheng added: “That’s one possible reason for fighting off the viruses a little bit better in the females compared to the males.”

Co-senior Dr. Tim O’Sullivan, assistant professor of microbiology, immunology and molecular genetics at the Geffen School at UCLA, elaborated and said their findings highlight the importance of understanding how NK cells are “programmed” to respond to a viral infection. In other words, quality over quantity.

O’Sullivan said it is possible that, in the future, immunotherapy treatment could be “female derived.”

“That seems to be a little bit more telling in terms of how an NK cell is going to control a viral infection,” O’Sullivan said. O’Sullivan explained that if you have a female NK cell with more of this epigenetic regulator UTX, it “programs an NK cell all the way from birth to have enhanced production of these effector molecules,” which are “potently antiviral.” 

That means that even if women have fewer of those NK cells, they work better — hence the “enhanced protection.” 

“Now you have maybe a little bit less of those NK cells, [but] they can do a better job of controlling viral infection,” O’Sullivan noted.

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Dr. Maureen Su, co-senior author and professor at the David Geffen School of Medicine at UCLA, told Salon their findings also highlight the need for scientists to take sex into consideration when developing immunotherapy responses and treating viral infections.

“We know that women get more autoimmune diseases,” Su said. “Clearly, there’s something really important about being male versus female here, and we have only started figuring out what it is.” If they can figure out these sexual differences, “maybe we can target it with therapies,” Su speculated.

O’Sullivan said it is possible that, in the future, immunotherapy treatment could be “female derived.”

“If they’re going to be better agents against cancer or better agents against infection, it’s something that we should be thinking about from the beginning of our treatment strategy,” O’Sullivan said. “I really think it moves us in a direction where we have to consider the sort of personalized therapies and use sex as a very important variable in determining those outcomes.”

“They’re going to have different regulatory mechanisms,” he continued. “Perhaps female cells will have better outcomes in certain settings and male cells might have better outcomes in other settings.”

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