Brian Lazzaro, Entomology, is all about fly genetics. But as he talks about his work, he takes a moment to bring up fast food.

“You can easily imagine that if you eat McDonald’s for lunch every day, that’s an environmental risk factor that’s going to increase your risk of heart disease,” he says. He adds, however, that certain people are going to be genetically more sensitive to eating at McDonald’s, while other people can better tolerate eating junk food without experiencing the same increased risk of heart disease.

“That’s where you have your genotype and environmental risk factor interacting,” he says. “It’s not just that one or the other leads to risk of disease—it’s more complicated.”

Flies with Varying Genetics and Environmental Quirks

Instead of studying people eating at McDonald’s, Lazzaro studies flies. Flies on varying diets, flies living in altered ambient temperatures, flies with different reproductive activity. Some overarching questions of Lazzaro’s research include: How do genetics and environmental factors contribute to altered defense against infection? What makes individuals and populations differ in their ability to fight infections? How much does the variability in immune system come from the environment versus genetics?

Lazzaro uses the most popular genetic model insect in his research, Drosophila melanogaster. But whereas most drosophila genetics labs study dramatic mutants, Lazzaro is focused on the genetic variation that is found in natural populations—“from the field,” as he says. Using flies with natural variation, Lazzaro and his lab can genetically map a variety of immunological traits, and then examine what genetic factors could lead to heightened or worsened immune performance under varying conditions.

Diets and Infection

In one study, the researchers in his group compared flies under normal diets to flies fed a high-glucose diet. They found that flies on the high-glucose diet were more susceptible to infection, implying that the bacterial pathogen feeds off of the extra sugar in the fly’s blood or that the extra sugar causes a metabolic dysfunction that alters immune performance in the fly.

More important, however, is that some flies had distinctly worse immune systems on the high-sugar diet and others maintained their relative immune performance despite the altered diet. Thus, some genetic variants are disproportionately susceptible to the sugar in the diet. The next step of the research is to determine how the implicated genes bridge metabolism and immunity.

Sex and the Immune System

In another study, Lazzaro’s lab discovered that female flies become significantly more susceptible to disease after mating, as compared to virgin flies. Immune capability immediately drops after the female fly mates—a distinct physiological change. Lazzaro, in collaboration with Mariana Wolfner, Molecular Biology and Genetics, is working to identify the molecular mechanisms for this “life history trade-off,” meaning the physiological and evolutionary “decision” of producing eggs or fighting off disease.

One hypothesis is that the major organ for feeding nutrients into the female fly’s eggs is the same organ that regulates immunity. That could literally put physical constraints on what the organ can accomplish, therefore limiting immunity in favor of provisioning the fly’s eggs.

Much like the study on high-sugar diets, Lazzaro is concerned with the female flies that exhibit more or less sensitivity to the immunological cost of mating. In both studies, he is interested in finding what leads to a stronger or weaker immune system. Lazzaro is also keen to understand the bigger picture of how environmental variability interacts with genotypes over the course of time.

“We’re not studying the immune system per se,” he says. “We’re more studying how the rest of the host interacts with the immune system—the overall physiological context—and we want to know about that both from a functional and an evolutionary perspective.”

Pathogens and Hosts

In line with this evolutionary work, Lazzaro is just as concerned with the pathogens that infect host flies to cause disease. In much of his lab’s work, researchers look at how host genes interact with and evolve in response to various pathogens.

For example, Lazzaro’s lab has compared the genes from immune systems of multiple drosophila individuals and species. They hypothesized that they would see the strongest natural selection on recognition proteins—the proteins that recognize the pathogen in order to activate an immune response. It makes sense because pathogens adapt in order to hide, then recognition proteins change in response.

In another study, Lazzaro’s lab discovered that female flies become significantly more susceptible to disease after mating, as compared to virgin flies.

But Lazzaro and his team discovered something totally unexpected. Recognition proteins were not adapting. Instead, they saw that signaling molecules inside the cell were evolving very quickly at the protein level, even though the same set of proteins has been used in all insects over hundreds of millions of years. The signaling proteins evolve much faster than anticipated, and that speedy process suggests a co-evolution with pathogens.

If a pathogen is unable to avoid recognition by the immune system but can depend on the signaling pathways being consistent across insects, then, Lazzaro says, “it’s a very good evolutionary strategy for the pathogen to just be able to block those pathways” and thereby eliminate the immune response. His lab is now in the process of testing to see whether this hypothesis holds true.

Putting the Details Together

Studying pathogens, environmental factors, and fly genetics all together is what makes Lazzaro’s lab unique. “If you put these things together, you can really ask, what does the pathogen want to do, what does the host want to do, what’s the environmental impact on that? You can really understand it as more of a system,” Lazzaro explains.

These questions are important to broader systems studies as well, he adds. “These same principles can apply to any kind of infectious system. It’s got to apply to humans who are acquiring infections out in their natural environment: there’s still a pathogen with something it wants to do, there’s a person with a natural physiology, there are environmental factors—all of that comes into play.”