Hemocytes pleiotropic effects on midgut homeostasis and immunity are agonists of Plasmodium falciparum infection

Plasmodium parasites cause malaria, which remains the deadliest of mosquito-transmitted diseases. For successful transmission, the malaria parasite must complete a complex infection cycle in the mosquito vector and survive attack from the insect’s innate immune system. Hemocytes (macrophage-like) are professional mosquito immune cells essential for cellular and humoral immune responses, including the production of anti-Plasmodium factors. Here, we show that hemocytes from the African malaria vector Anopheles gambiae have a pleiotropic function unrelated to immunity. We found that hemocytes control intestinal stem cell proliferation, help to maintain the midgut epithelial integrity, and modulate the microbiota load by regulating the expression of AMPs in the midgut. Depleting hemocytes disrupts these functions, producing a high mortality rate and unexpectedly reducing the number of oocysts of the human malaria parasite Plasmodium falciparum. Interestingly, these new hemocyte functions are triggered upon the blood meal, and the parasite takes advantage of them to evade the immune response. This work shows for the first time that hemocytes have functions beyond immunity. In addition, we are showing that hemocytes are agonists of P. falciparum and not antagonists, as occurs with the rodent malaria parasite Plasmodium berghei. These findings highlight the necessity of considering the differences in mosquito immune responses against different Plasmodium parasites to generate better strategies for malaria control.