Targeting Mosquito Immunity to Fight Disease
Before a mosquito can transmit a disease like dengue fever, Zika, or malaria to a human, the mosquito itself must get infected. That means the parasite or virus must find a way around the natural defenses of the insect’s immune system.
But what if we could manipulate mosquitoes so that they could effectively fight off an infection before transmitting disease, or if they could resist becoming infected altogether?
These questions are at the heart of the research of Penn’s Michael Povelones. An assistant professor in Penn’s School of Veterinary Medicine, Povelones investigates the mosquito immune system for clues as to how those defenses may be targeted to control diseases that mosquitoes spread—infections such as malaria, dengue, chikungunya, yellow fever, and Zika, which claim the lives of hundreds of thousands of people worldwide each year.
“For a long time, mosquitoes have been a major focus for controlling diseases like malaria and dengue, through approaches like insecticide treatments,” Povelones says. “In fact, right now Florida is conducting aerial insecticide spraying to kill the mosquitoes responsible for transmitting Zika.
“Our lab is trying to take a more sophisticated approach, working to understand the mosquito’s natural defense systems that we can hopefully exploit in the future to try to combat these diseases.”
To do so, Povelones and his lab members study the immune systems of mosquitoes in a state-of-the-art insectary at Penn Vet. Designed with many features to prevent any mosquitoes from escaping—including sealed air vents and drains, light traps that are routinely monitored, negative air pressure, and separate rooms for different tasks—the facility is where the researchers rear roughly 10,000 mosquitoes each week. Povelones jokes that he’s far more likely to get bit by a mosquito while walking around campus than in his laboratory.
In order to understand how different components of the mosquito’s immune system play a role in responding to pathogens, Povelones and his lab members often conduct gene silencing experiments, in which they use double-stranded RNA to temporarily disable a gene of interest. They then challenge the genetically modified mosquito with a pathogen and monitor how it responds.
Recently, Povelones and colleagues at Imperial College London and the American University of Beirut used this technique to uncover previously unknown components of the mosquito immune system that slow down the immune response against malaria. The researchers discovered that these molecules, C-type lectins, negatively regulate the mosquitoes’ complement system and could potentially serve as targets for an intervention that stops the malaria parasite from moving beyond the mosquito.
“If we could remove the brakes of the immune system,” says Povelones, “we might get a really robust attack of the pathogen inside the mosquito.”
With a new grant from Penn Vet’s Center for Host-Microbial Interactions, Povelones has also been collaborating with the Perelman School of Medicine’s Sara Cherry, an associate professor of microbiology, to understand how the mosquito microbiome—the collection of bacteria, viruses, and other microbes that populate the gut—is regulated, and how its composition influences the likelihood a mosquito will become infected with the viruses that cause dengue and Zika.
“We’re starting to investigate the possibility that a mosquito’s microbiome could be ‘primed’ to resist infection and prevent viral transmission,” Povelones says.
Though the lab’s work is firmly rooted in basic science and discovery, Povelones says they are laying the groundwork for interventions that may one day be used to reduce the burden of mosquito-borne disease.
“There’s been a lot of investments made recently in thinking about using transgenic mosquitoes to prevent disease transmission in the field,” he says. “Where our research intersects with that is we’re providing the basic knowledge and molecules that we’d like to target in some of those future plans.”