When it comes to studying viral infection, the human immune system has long stolen the spotlight. Scientists have spent decades puzzling over how this complex suite of defenses evolved to fight and survive deadly viruses, and the many ways in which immune systems can vary between populations, age groups and even gender. But it takes two to tango—in this case, the immune system and its invader. And so far, much less attention has been paid to the thing actually doing the infecting.
That’s a shame, because viruses may be far more savvy than we give them credit for. Now, new research suggests that some sneaky pathogens have evolved to take into account one particularly important factor about their hosts: their gender. A study published yesterday in the journal Nature Communications finds that the leukemia virus may have evolved to go easier on some human women, presumably to increase its chances of being passed on to their children.
In other words, viruses might understand the differences between the sexes better than we do. “This is a very nice example of how the evolution of the pathogen really has a bearing on health and medicine,” says Vincent Jansen, a mathematical biologist at Royal Holloway University and lead author of the study. “I think that is something that has not always been appreciated before.”
Just as men and women have developed different strategies to cope with society’s slings and arrows, so have their immune systems. In general, women tend to mount much more aggressive attacks on infections, which can help clear them up faster but can also lead to more intense autoimmune reactions to diseases and vaccines. Biologists still debate the reason for this discrepancy, but they suspect that it could have to do with the different levels of hormones in men and women, or with differently expressed genes between the sexes.
Yet until now, biologists hadn’t looked deeply into how viruses could take advantage of gender differences. In fact, Jansen said that he was initially quite skeptical when his colleague at the university, biologist Francisco Úbeda, first wondered whether it was possible that pathogens could have evolved to affect the sexes differently. “I was expecting that viruses or bacteria have a one-size-fits all strategy when it comes to male and female hosts,” Jansen says.
However, after Úbeda built a mathematical model of evolution that showed it was theoretically possible, Jansen decided to hunt for real-world data to see whether it was actually true. "That is not as easy as it sounds," Jansen says.
He and Úbeda needed a detailed data set to see how a disease could affect a particular group of people. They found that data in epidemiology statistics from studies looking at thousands of people on Human T-Cell Lymphotropic Virus-1, a virus that can turn into Adult T-Cell Leukemia in roughly 1 to 5 percent of infected people. Jansen and Úbeda specifically compared how often infections led to leukemia among men and women in the Caribbean versus Japan, without examining cultural or age-related factors.
In Japan, women tend to breastfeed their babies for several months more on average than women in the Caribbean, according to data from the World Health Organization. This appears to be a key difference that has driven the virus to tamp down its lethality among women in Japan. Rates of leukemia development from infection are roughly equal among men and women in the Caribbean, Jansen says, while women in Japan are about three times less likely to develop leukemia from the virus. Adult T-cell leukemia or lymphoma kills about 50 to 90 percent of people who develop it within 4 to 5 years.
Women in Japan breastfeed for longer, Jansen says, which offers the virus more opportunities to spread from mother to child. Thus, it would be advantageous for the virus to be less lethal to women there, and infect the next generation. “What I had not appreciated was that, although male and female bodies work in similar ways, from the point of view of the pathogen there can be big differences,” Jansen says. “The fact that women can transmit to their children and men cannot is one such difference.”
Data on the transmission of the virus in Japan appears to corroborate Jansen’s model: There are more cases of the virus and leukemia found passed within families there, he says.
Jansen hopes his research could help spur further study into how exactly the viruses are able to modify their effects on the different sexes. He says that could lead to techniques to "trick" a pathogen into thinking it has infected a woman, perhaps through manipulating whatever factor the pathogen is using to detect the person’s sex, to reduce its effects. "This is a very nice example of how Darwinian medicine could be used," Jansen says.
Sabra Klein, a biologist at Johns Hopkins University who was not involved in this study, says she appreciates that the authors took a new perspective on evolution and infection by homing in on the virus itself. However, she says that their model ignores many other factors, ranging from culture to age, that could influence a pathogen's effect on the sexes.
"It is refreshing to consider that pathogens may evolve different virulence depending on whether they are replicating in male or female hosts," says Klein, who has published extensively on the different immune responses of men and women. However, she says, "I think that their title should have better reflected the limits of the model because from the title and even the abstract it assumed that this model explains all sex-specific infectious diseases." (The paper’s title is “The evolution of sex-specific virulence in infectious diseases.”)
Klein points out that other viruses with sex-specific characteristics might transmit and replicate very differently than the leukemia virus. For example, she cites the Zika virus, which is transmitted not only person-to-person through sexual contact and from mother-to-child, but also through mosquitoes. “In the case of Zika virus, women, even non-pregnant women suffer more severe disease (and have a higher incidence) than males in Puerot Rico,” Klein says. “How would their model explain [this]?”
Middle Tennessee State University biologist Erin McClelland agrees with Klein's critiques, but also with Jansen and Úbeda's assertion that more research should be done on the process of infection from the perspective of the pathogen, not just the host. "If we can start to untangle both sides of the equation," McClelland says, "we can really start working on gender-specific therapeutics for pathogens that show a sex bias." Those therapies could involve tailoring drug regimens to better work in men versus women, she adds.
In other words, it's time to take a page out of the pathogen's book.