While it’s easy to think about mosquitoes as a mere portal for shuttling malaria and other diseases from one person to another, the insects have their own immune response to infection. After sucking blood, mosquitoes ramp up production of immune system proteins to fight off potential parasites.
“This appears to be a new mechanism by which the mosquito is anticipating a parasite infection,” says Michael Povelones, assistant professor in the School of Veterinary Medicine at University of Pennsylvania.
How do they do it?
A greater understanding of how mosquitoes naturally fight off infection could offer a way to prevent people from getting infected with those same pathogens, researchers say.
“With malaria and other vector-borne diseases, we’re faced with problems of not having effective vaccines, drug-resistant parasites, and insecticide-resistant vectors,” Povelones says. “
Researchers already knew that a group of molecules called leucine-rich repeat immune proteins, or LRIMs, were important players in mosquitoes’ immune defense.
In a paper published in 2009 in the journal Science, Povelones and coauthor George K. Christophides, professor and chair of infectious diseases and immunity at Imperial College London, reported that two of these LRIMs are part of a signaling pathway akin to the human complement system, which coordinates immune response through a cascade of signaling interactions.
In the current study, published in the Journal of Innate Immunity, Povelones and Christophides wanted to gain a deeper understanding of what the other identified LRIM proteins—there are at least two dozen—do for mosquito immunity.
Using RNA inhibitors, which block production of particular RNA transcripts, they “turned off” one LRIM at a time in live anopheles gambiae mosquitoes. Then, they exposed the insects to plasmodium berghei, a parasite that is related to plasmodium falciparum, which causes malaria in humans.
The plasmodium berghei parasite only infects mammals other than humans, making it a good, safe model for studying malaria.
From their tests, one protein, LRIM9, stood out. When it was blocked, parasite levels in the mosquitoes increased three-fold. And they found that adult females had the highest expression levels of LRIM9, with more than 20 times the amount of LRIM9 as adult males. LRIM9 RNA expression was also low in earlier life stages, such as in eggs and pupae.
“That was the first good clue that we were looking at something unique that we hadn’t seen before,” Povelones says. “That turned the focus toward blood feeding.”
Adult females are the only mosquitoes that drink blood, leading the researchers to consider whether it was something about this meal that triggered activation of Mosquitoes were fed blood from mice that were either infected with P. berghei or were uninfected. No matter whether the insects drank the infected or uninfected blood, LRIM9 levels surged 48 hours after their meal.
That finding still left open the possibility that there were pathogens besides P. berghei in the blood to which LRIM9 was responding. Previous research has shown that bacteria enter the mosquito’s gut following blood meals, dramatically expanding the population of microbes already present.
But LRIM9 levels rose even when the mosquitoes were given antibiotics before feeding, indicating that the bacteria weren’t responsible for triggering LRIM9.
Since it appeared that the parasites and bacteria weren’t responsible for activating LRIM9, the researchers wondered if hormones might be playing a role. They zeroed in on ecdysone, a steroid hormone secreted by the ovaries after blood feeding that regulates genes important to reproduction.
After injecting mosquitoes with 20E, the biologically active form of ecdysone, production of the LRIM9 protein increased. Though ecdysone is associated with reproduction, and specifically egg formation, in mosquitoes, LRIM9 didn’t impact reproductive success. It also didn’t affect the mosquitoes’ digestion.
In a final test, the researchers checked to see whether LRIM9 acted in the same pathway as LRIM1 and APL1C, but found no evidence to support its involvement. “We can’t be 100 percent sure we’re dealing with a new pathway, but it doesn’t seem to be related to the system we already knew about,” Povelones says.
LRIM9 may help the mosquito immune system recognize pathogens and may also recruit or interact with other immune system components, the researchers say, so beefing up its levels could quicken an immune response, before a parasite is even detected.
