Molecular observations by UC Santa Cruz scientists demystify parasitic mind control
Using brain mapping, genetic engineering and machine learning, scientists reveal how parasitic bacteria take over fruit fly brains.
Some parasites can hijack the behavior of the animals they infect. Grasshoppers colonized by hairworms will jump into water, where the worms can reproduce. Toxoplasma gondii causes mice to stop fearing cats, delivering the parasites to their favorite haunt – feline intestines. While scientists have documented numerous ways parasites influence their hosts, the neural and molecular mechanisms behind this mind control are poorly understood.
New research from the labs of UC Santa Cruz professors Bill Sullivan and Grant Hartzog reveals how one bacterial parasite, called Wolbachia, alters the mating behavior of the fruit fly, Drosophila melanogaster. The study, published on May 9 in Cell Reports, identifies the neurological basis of this behavior change.
“It’s a real step forward in understanding the molecular mechanisms behind this behavioral modification,” said Brandt Warecki, a postdoctoral researcher in Sullivan’s lab and the study’s lead author.
Exposing Wolbachia’s strategies
Wolbachia infects over 40% of all insect species and is exclusively passed on through the eggs of infected female parents. Because of this, Wolbachia can only spread through a population if infected female flies possess a reproductive advantage over uninfected females. In Drosophila melanogaster, this edge can be attributed to Wolbachia’s ability to produce a zeal for mating in infected female flies.
And beyond making fruit flies friskier, the researchers say Wolbachia can make them more adventurous: The parasite can even drive infected flies to mate with other species, “which is pretty crazy,” Warecki said.
Explaining Wolbachia‘s mind control powers required understanding how the bacteria alter the function of the female flies’ brains. First, the researchers had to track the parasite down. Using UC Santa Cruz’s advanced microscopy facility, the team discovered that Wolbachia localizes to parts of the fly brain controlling sensory perception and decision making.
The team collaborated with Timothy Karr, a researcher at Arizona State University, to compile a dataset of the proteins whose quantities differed in the brains of infected and uninfected flies. One of these proteins was a receptor protein found in neurons. In infected brains, this receptor was significantly downregulated, suggesting that it was a likely target and the mechanism by which Wolbachia regulates host behavior.
Reverse engineering mind control
Warecki and colleagues next tested if downregulation of the receptor protein alone can explain the increased mating of infected female flies. They genetically engineered uninfected fruit flies to reduce the levels of the neuronal receptor in the same neurons colonized by Wolbachia. The gene-edited fruit flies showed the same supercharged mating behavior seen in Wolbachia-infected flies.
According to Sullivan, Drosophila melanogaster is one of the few species that could be genetically engineered with enough precision to perform this experiment, owing to the sophisticated molecular and genetic techniques developed over decades of research in this key model organism.
“We reached a point with Drosophila in which we can knock out a given gene in a specific cell type at any time in development,” he added.
Once the team determined that this neuronal receptor is an important target for Wolbachia, they used a machine learning algorithm to identify Wolbachia-produced proteins that might be interacting with the neuronal receptor. When specific proteins land in a neuron receptor, they regulate the activity of the neuron, driving brain function. But the shape of each receptor will only accommodate one specific protein, “just like a baseball and glove,” Sullivan said. Machine learning enabled the team to identify a Wolbachia protein (“baseball”) that likely targets the neuron receptor (“glove”).
This provided a detailed understanding of how Wolbachia was steering the flies’ mating preferences. The results of this study, Warecki said, can inform future research examining host-parasite interactions in other species.
The benefits of curiosity
The history of Wolbachia research, Sullivan said, provides an example of how curiosity-driven, basic research can lay the foundation for life-saving discoveries. Until the early 2000s, researchers studied Wolbachia as a “curiosity”, with no specific applications in mind. Soon, scientists realized the myriad health applications of their research.
One example was the realization that Wolbachia suppress the replication of some viruses in their insect hosts. This finding directly led to large scale public health programs in which Wolbachia is introduced into mosquito populations carrying the devastating Dengue virus. The results have been encouraging: Dengue cases have been dramatically reduced in the afflicted regions.
“Wolbachia is such a wonderful story about the importance of curiosity-driven research,” Sullivan said. Furthermore, as Hartzog noted, “this sort of impactful work is exactly what we were hoping for when we launched our program in Global and Community Health.”
The UC Santa Cruz study on Wolbachia’s influence over fruit fly behavior was itself funded through a grant from the National Institutes of Health National Institute of General Medical Sciences; an institute dedicated to supporting “basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.”
