For people living in the Northern hemisphere, mosquitoes are more of an annoyance than a real threat. However, in many other areas of the world they pose serious health risks as they transmit devastating infectious diseases such as malaria caused by the Plasmodium parasite. Each year, more than two hundred million humans are infected, and almost one million die from malaria, mostly children under 5 years. To interrupt this dramatic cycle of infection and death, scientists around the world have analyzed the immune response against Plasmodium in the human host, but only a few have surveyed the mosquito's immune response. In a study published recently in Science, researchers from the National Institutes of Health led by Carolina Barillas-Mury have shown that mosquitoes are able to develop long-lived immunity to Plasmodium.

For someone suffering from malaria it is cold comfort to know that the mosquito may also suffer after being infected by the parasite. While the mosquito's immune system attacks the parasite to fight off infection, they lack an adaptive immune response, which remembers previous infections and bolsters a highly specific response after re-infection. Therefore they rely primarily on their innate immune system, which, according to current textbooks, has no memory. However, a few recent studies indicated that insects may have developed other strategies resulting in a specific immune priming that enhance phagocytic responses after renewed infection with the same pathogen.

To investigate whether mosquitoes develop antiplasmodial immunity in response to subsequent infections, the team fed two groups of mosquitoes with blood carrying the infectious stages of the parasite. One group was kept at a temperature that could allow the infection to develop (referred to as primed mosquitoes), while the other group was incubated at higher temperatures, which prevents development of the parasite and hence blocks the infection (referred to as naïve mosquitoes). After 7 days, they fed the mosquitoes again with blood containing the parasite, but this time they allowed the infection to become established in both groups and determined the number of parasites in the mosquitoes to obtain a measure of the strength of the antiplasmodial immune response. The scientists found that the number of parasites was significantly reduced in the group of primed mosquitoes. Hence, the mosquitoes had developed some kind of immune memory as they learned from the first infection and were much more effective in fighting off the second infection. But how do they fight the parasite?

As the innate immune system of insects is largely based on the activity of immune cells (called hemocytes in insects), the scientists went on to analyze these cells in both groups of mosquitoes. They focused on one subpopulation of hemocytes called granulocytes, which are known to be involved in killing invading microorganisms. Indeed, the number of granulocytes was permanently raised in the group of primed mosquitoes. Next they tested whether the hemolymph of the primed mosquitoes contained specific factors that could confer an enhanced immune response. Having injected cell-free hemolymph from naïve and primed mosquitoes into parasite-free recipient mosquitoes, the team then exposed these insects to malaria parasites to see whether any factor(s) in the cell-free hemolymph might bolster the mosquito's immune response. It did. The mosquitoes that had received hemolymph from the primed mosquitoes had an enhanced antiplasmodial immune response and an increased number of granulocytes.

So Carolina Barillas-Mury and her colleagues have shown that mosquitoes have an immune memory that helps them fight off Plasmodium infection, and once the soluble hemolymph factors involved in conferring antiplasmodial immunity in mosquitoes have been identified, they may open up new strategies that target the mosquitoes' immune response to fight malaria.

F. A.
L. C.
Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes