A mouse study has revealed a possible difference between the immune systems of women and men.

Why do men get sicker from viruses than women? New study could help explain 'man flu'

Women appear to have fewer, but stronger, natural killer cells.

‘Man flu’ has become an established phrase when joking about how men complain more than women when they have a cold or the flu.

However, some scientific research now suggests that men actually do become sicker from viral infections.

Men have a greater risk of developing severe symptoms of COVID-19 and dying than women, according to a 2022 study in the journal Immunology.

In general, women appear to have stronger immune responses and respond better to vaccines.

On the flip side, women have a greater chance of developing autoimmune diseases, where the immune system attacks its own tissue.

Differences in the immune system

The differences may have to do with the fact that women have two X chromosomes and men one. Hormones can also play a role. In addition, lifestyle might have something to do with it.

In a new study from 2023, researchers at the University of California, Los Angeles (UCLA) uncovered a possible difference between the immune systems of men and women.

This might help to explain gender differences in how men and women react to viral infections. The results have been published in Nature Immunology.

An extra copy

Researchers have studied the significance of the gene and protein UTX. Women and female mice have an extra copy of this gene because the gene is on the X chromosome, which women have two of.

Erik Dissen is a professor and immunologist at the University of Oslo. He says that in women the genes in one X chromosome are switched off, called X-chromosome inactivation.

“One X chromosome is turned off. Each cell chooses one or the other early in foetal life, and this choice is inherited when the cells divide further in the body.”

However, not the entire X chromosome is turned off. In humans, about 20 percent remains active. Women have a double dose of these genes.

Women have fewer but stronger killer cells

The researchers at UCLA found that the UTX gene and the protein it codes for are important for the function of natural killer cells.

Natural killer cells, or NK cells, are part of our innate immune system – the first line of defence against invaders in the body.

NK cells can kill cancer cells or cells infected by viruses.

Scientists have known that men often have more natural killer cells than women. One would therefore imagine that men have a better defence against viruses. But that doesn't seem to be the case.

The new study comes with a possible explanation.

Since women have double the UTX gene, they have more of the UTX protein in their natural killer cells. The experiments in the study indicate that a double dose of UTX means that despite fewer of these cells, they are better able to protect against viruses.

“It turns out that women have more UTX in their NK cells than men, which allows them to fight viral infections more efficiently,” Dr. Maureen Su, who participated in the study, said in a press release.

Did a series of experiments

The researchers have mainly carried out their experiments on mice.

In a series of experiments, they showed that natural killer cells from male mice and men reacted more weakly to threats than the killer cells from female mice and women in the laboratory setting.

Furthermore, male mice had more natural killer cells.

This difference held true even when mice had their testicles or ovaries removed. The male mice still had more natural killer cells which reacted more weakly, indicating that the difference is not primarily linked to sex hormones.

The researchers then investigated which genes might be behind the difference and narrowed it down to UTX, of which women and female mice have an extra copy.

They edited female mice so that one copy of the gene was deleted. The female mice then developed more natural killer cells, like male mice.

The researchers conducted several more experiments that suggest that the amount of UTX controls the number of natural killer cells and improves their ability to deal with threats.

Mice that had UTX completely knocked out died from viral infections.

“Just knocking out one gene was the difference between whether the mice survived or died in this model,” says Dissen.

Do men get sicker?

Dissen is an expert on natural killer cells and says that the study is interesting and has received a lot of attention within the research community.

The topic of gender differences was made real with COVID-19, when men clearly suffered serious illness more often than women.

But is it generally the case that men get sicker from viruses? That’s not entirely clear.

“The term ‘man flu’ is a slightly sarcastic term suggesting that men are more whiny when they get sick,” says Dissen.

“However, it is actually possible to measure systematic differences if you look at enough women and men and how they respond to viral infection. Signalling substances in the blood are one way to do this,” says Dissen.

“Then you can see differences. It looks like men produce a little more of the substances that cause fever and make you feel ill.”

Dissen adds that this remains difficult to research, because the immune system contains so many different cell types and signalling substances.

Can't always blame gender differences

Women may be slightly less susceptible to viral infection, but they are much more susceptible to autoimmune disease, says Dissen.

“To put it simply, women’s immune systems may have a greater inflammatory and more powerful immune response when it comes to viral infections. But they may also be more aggressive towards their own cells and tissues and develop autoimmune reactions because of that.”

Dissen also notes that in the discussion about gender and viral disease, we need to remember that the differences between individuals are probably greater than between genders.

“The difference within a range of women is probably greater than between men and women,” he says.

It isn’t like the man is always the sickest in cases where both members of a couple have the flu.

“Individual differences include a whole lot of genes that have nothing to do with gender – like environmental factors,” says Dissen.

Mice lived in a protected environment

Can the new study explain why men became sicker from COVID-19?

It’s possible that the researchers’ discoveries might have played an important role. But for now, Dissen believes, it’s too early to say.

An important limitation of the study is that it was done on mice – and mice that lived in a clean, virus-free environment.

“But the researchers have in fact identified a gene that appears to contribute to the NK cells in female mice being more activated and ready to fight than they are in males.”

Dissen believes it is currently unclear whether the same applies to humans.

“The NK cells are basically pretty nice and calm. They have to be activated a bit by other signalling substances in the immune system before they go and kill something.”

The mice in the lab are caged and protected from infection. Their killer cells are more dormant than is natural.

“Whereas if you look at an ordinary person, we’re exposed to bacteria and viruses all the time. The NK cells would then tend to be more on the alert.”

Perhaps the fact that the NK cells are on high alert can lead to the difference between male and female NK cells evening out in people who are constantly exposed to infection.

Unexpectedly clear results

Having said that, Dissen still thinks the results that the researchers can point to are unexpectedly strong.

“The fact that just having half a dose of the gene has such a great effects, I find quite interesting.”

Dissen points out that the UTX gene has several tasks in a cell. It helps to decide whether genes should be used or not.

“Let's say that all the cells in the body have 20 000 genes that they can choose from to read and use – or not. Epigenetic factors determine whether the cells will activate a gene or not.”

UTX determines which genes are to be open for use and which should be closed again. It does this together with many other molecules that work together.

Better understanding

It is currently too early to say whether the findings in the new study could have an impact on treatment, says Dissen.

“But this type of research helps us understand the variation between men and women.”


Mandy I. Cheng, et.al.: The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature Immunology, 2023.


Read the Norwegian version of this article at forskning.no

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