Prostaglandins regulate humoral immune responses in Aedes aegypti

Prostaglandins (PGs) are immuno-active lipids that mediate the immune response in invertebrates and vertebrates. In insects, PGs play a role on different physiological processes such as reproduction, ion transport and regulation of cellular immunity. However, it is unclear whether PGs play a role in invertebrate's humoral immunity, and, if so, which immune signaling pathways would be modulated by PGs. Here, we show that Aedes aegypti gut microbiota and Gram-negative bacteria challenge induces prostaglandin production sensitive to an irreversible inhibitor of the vertebrate cyclooxygenase, acetylsalicylic acid (ASA). ASA treatment reduced PG synthesis and is associated with decreased expression of components of the Toll and IMD immune pathways, thereby rendering mosquitoes more susceptible to both bacterial and viral infections. We also shown that a cytosolic phospholipase (PLAc), one of the upstream regulators of PG synthesis, is induced by the microbiota in the midgut after blood feeding. The knockdown of the PLAc decreased prostaglandin production and enhanced the replication of Dengue in the midgut. We conclude that in Ae. aegypti, PGs control the amplitude of the immune response to guarantee an efficient pathogen clearance. Author summary Mosquito immune responses work on an on/off switch model, where the recognition of microorganisms turns the switch on, and its clearance turns it off. Besides pathogen derived molecules, no other compounds are known to directly regulate the activation and the amplitude of immune responses. Here we described that prostaglandins, lipid mediators of the immunity in vertebrates, also modulate the amplitude of immune responses in mosquitoes as well. Prostaglandins regulate the production of antimicrobial peptides and other effector molecules and directly impact the susceptibility of mosquitoes to bacterial and viral infections. When prostaglandin production is impaired, immune activation is inefficient and renders the mosquito more susceptible to bacterial and Dengue infections.