Behind the Headlines

Monday May 18 2009

The study did not prove whether man flu exists or not

“Man flu is not a myth: female hormones give women stronger immune systems,” reported the Daily Mail. It said researchers have found that oestrogen helps the immune system fight off bacteria and other invaders, and suggested that men’s defences might benefit from oestrogen-based drugs.

The research this story is based on did not look at infection with flu viruses, and cannot prove whether ‘man flu’ exists or not. In addition, the study was in genetically engineered mice, so the results are not necessarily applicable to humans. The research shows that introducing the human form of the gene caspase-12 has differing effects on susceptibility to infection with one type of bacteria in male and female mice. As such, it is not clear whether the results apply to infection with other bacteria or viruses, or whether there are similar gender differences in immunity in humans.

Where did the story come from?

The research was carried out by Dr Garabet Yeretssian and colleagues from McGill University in Canada and other Canadian and US research centres. The work was funded by the Canadian Institutes for Health Research and the Canadian Foundation for Innovation. The study was published in the peer-reviewed scientific journal Proceedings of the National Academy of Sciences of the USA.

What kind of scientific study was this?

This animal study looked at the role of the protein caspase-12 in infection in mice. Previous studies have shown that caspase-12 reduces the body’s immune response to certain types of bacteria, and suggest that it increases the risk of sepsis, an extreme inflammatory response to infection that can be lethal. Humans have the gene for caspase-12, but most people have a mutated version of the gene that does not produce a functional caspase-12 protein and therefore does not have this effect on the immune system. However, it is estimated that 20% of people of African descent do not have this mutation, and so produce a caspase-12 protein that works.

To investigate the role of this protein further, the researchers genetically engineered mice to lack the mouse caspase-12 gene and carry the human caspase-12 gene instead. They then looked at whether normal mice, mice lacking the mouse caspase-12 gene and those carrying the human form of the gene responded differently to infection with Listeria monocytogenes bacteria. These bacteria cause a disease called listeriosis, a serious form of food poisoning. Mice were injected with the bacteria, and for the next four days the researchers measured the level of bacteria in the spleens and livers of the mice.

The researchers also investigated whether response to infection in these mice would be affected by gender, as previous studies in humans and animals suggest that males and females handle infection differently. The experiment therefore included equal numbers of male and female mice in each experimental group (48 males and 48 females in total). Of these 96 mice, 32 were normal, 32 lacked the mouse caspase-12 gene and 32 had the human caspase-12 gene. Each day the levels of bacteria were assessed in four mice of each gender from each group.

If there were differences in response to infection in male and female mice, these could be due to the female hormone oestrogen. Therefore, the researchers tested whether the hormone oestrogen affects the activity of the human caspase-12 gene. To investigate this, they looked at whether male and female mice produced different levels of human capase-12 during infection. They also injected infected male mice with oestrogen and looked at whether this had an effect on their production of the human caspase-12 protein and at the levels of bacteria in their livers and spleens.

What were the results of the study?

The researchers found that mice lacking caspase-12 were resistant to infection by Listeria monocytogenes bacteria. This was demonstrated by lower levels of the bacteria in the spleen and liver than normal mice, four days after infection. When the human caspase-12 gene was introduced into mice lacking mouse caspase-12, the male mice became as susceptible to Listeria infection as normal mice, but female mice did not. By the second and third day after infection, the female mice carrying the human caspase-12 gene were similarly resistant to Listeria to female mice lacking the caspase-12 gene entirely. By day four after infection, the female mice carrying the human caspase-12 gene had levels of Listeria in the liver and spleen that were between the levels seen in normal mice and mice lacking caspase-12.

When infected with Listeria, the male mice produced more human caspase-12 protein than female mice. Production of this protein could be reduced by injecting male mice with oestrogen.

The oestrogen-treated males had an increased susceptibility to Listeria infection, shown by the fact that the levels in the spleen increased to the levels seen in female mice. However, when treated with oestrogen, the male mice with the human form of the caspase-12 gene were similarly resistant to infection to the male mice lacking the caspase-12 gene.

What interpretations did the researchers draw from these results?

The researchers suggest that “through oestrogen production, females have a built-in mechanism that prevents [caspase-12] from being expressed, favouring more robust inflammatory and immune responses to pathogens”. They suggest that the fact that giving oestrogen to males reduced caspase-12 production and increased resistance to infection “may have important therapeutic implications for managing infectious diseases in the African population”.

What does the NHS Knowledge Service make of this study?

Although this study increases scientists’ understanding of the role of the caspase-12 protein in infection, and how it is affected by oestrogen, the study has limited direct implications for human health, and the findings are over-interpreted in some of the newspapers.

Although a human gene was used on the study, the experiments were carried out in mice, and results may not be applicable to humans. In addition, even if a similar phenomenon was found to occur in humans, most people do not have an active caspase-12 gene, and therefore the results would only apply to a small proportion of people.

Only one infectious agent was used in this study: a bacterium called Listeria that causes food poisoning. Flu is caused by a virus, as are most colds. The mice in this study may have responded differently if they had been infected with a virus. These results cannot be directly extrapolated to infer a gender difference in flu in humans.

Links to the headlines

Hormone is aid to girls' protection. Daily Mirror, 14 May 2009

Women 'fight off disease better'. BBC News, May 13 2009

Men succumb to manflu because women have stronger immune systems, claim scientists. The Daily Telegraph, May 12 2009

Man flu is not a myth: Female hormones give women stronger immune systems. Daily Mail, May 13 2009

Man flu: it really does exist, girls. Daily Star, May 14 2009

Links to the science

Yeretssian G, Doiron K, Shao W, et al. Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection. PNAS 2009; Published online before print May 15

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Analysis by Bazian

Edited by NHS Choices