When a female Anopheles mosquito has its blood meal from a person containing the Malarial parasite, the gametes (parasite equivalent of eggs and sperm) are passed on to the mosquito’s gut cells. There, the cells fuse to form an ookinete which goes through a few more steps of development transforming itself into a form that subsequently lodges in the salivary gland of the mosquito. When the mosquito takes its next blood meal from an unsuspecting human, the parasite is successfully transferred to her resulting in Malaria. Why does the mosquito never get Malaria?
Just as in humans, mosquitos also have immune cells circulating in their hemolymph (blood equivalent in mosquito) that descend on the parasite infected gut cells and initiate a chain of reactions to clear out the ookinetes. Although the proteins that the mosquito gut cells make as well as recruit from the hemolymph in order to clear out the parasites is known, a new study explores the immune cells’ role in kicking off this cascade (1). The immune cells of the mosquito were labelled with a dye and then the mosquito was subsequently allowed to take a blood meal from a mouse infected with one of the Malarial parasites. When the authors observed the infected gut cells, they found that about 33% of them were found associated with a dye-labelled piece from the immune cells. This piece of the cell in scientific terms is referred to as a vesicle, and usually carries proteins and other molecules. Greater the number of ookinetes in the mosquito midgut, higher the number of vesicle forming immune cells found associated with them. However, in the same gut, the non-infected gut cells were not found to be associated with these immune cell-derived vesicles.
Upon sensing parasite infection, the mosquito gut cells activate a bunch of proteins that attach a nitro functional group (-NO2) to the parasite proteins. This process called as nitration ‘tags’ the parasite ookinetes and is then followed by the death of the infected gut cells and leaking of the ookinetes into the surrounding lumen. There another patrolling protein called TEP1, whose job is to clear out pathogens like the malarial parasite, springs into action. TEP1 protein breaks into a smaller piece and starts coating the surface of the ookinete thus marking it for clearing. So the mosquito clears out most of the ookinetes to be able to warrant a Malarial infection (2). The few that escape, are able divide multiple times to generate thousands of sporozoites that ultimately rest in the mosquito salivary gland (2). Going back to the study, the authors asked what would happen if they blocked the formation of these vesicles by the immune cells. Would it affect the subsequent clearing of the ookinetes? They found that the levels of the proteins required for nitration of the ookinete as well as the coating protein TEP1 were unaffected when immune cell-derived vesicle formation was thwarted. However, TEP1 did not bind well to the ookinetes and TEP1 bound ookinetes decreased from 90% to 50%. So they were not cleared out efficiently.
Since the process of nitration was previously shown to be at the start of this anti-parasite activity, the authors also tested if nitration triggers the release of these vesicles from the immune cells. A loss of proteins required for nitration in the gut cells, resulted in a 7fold decrease in the formation of the vesicles from the immune cells. Increasing nitration had the opposite effect; vesicle formation increased by 2 fold. They also found that putting the immune cells in contact with pre-nitrated gut cells was sufficient to promote vesicle formation by the immune cells. So what might be the ‘secret sauce’ in these immune cell-derived vesicles that might help mosquitos get rid of the parasite before Malaria sets in? Vesicles contain enzymes and other proteins and the authors imply that there could be one or several of them functioning to promote efficient binding of the TEP1 protein to the ookinete surface and help clearing it away.
Malaria affects millions of people each year and the parasite’s complex life cycle shared between mosquitos and humans is part thwarted in the mosquito successfully. How can we take advantage of a mosquito’s ability to fight off the malarial parasite and prevent transmission into humans? What about the role of the mosquito gut microbiota that also contribute positively to this process? Scientists continue to be busy uncovering the mosquito’s clever means to mount an effective defense against the evasive malarial parasite.