Influence of prostaglandin E2 on insect innate immune function

PROJECT SUMMARY Prostaglandins are important bioactive signaling lipids with key roles in the regulation of inflammation and innate immune function in both vertebrate and invertebrate systems. Derived from arachidonic acid, prostaglandins mediate conserved physiological responses in response to pathogen-associated signals that stimulate the activation, maturation, and migration of innate immune cells, conferring immune protection to infection. This includes mosquitoes, where prostaglandins have previously described roles in anti-pathogen immunity, immune cell function, and in mediating immune priming. Yet, despite the integral roles of prostaglandins on mosquito immunity, studies of prostaglandins have been limited, leaving significant questions as to how prostaglandins influence the mosquito innate immune system unanswered. Therefore, the overall objective of this application is to examine the contributions of prostaglandin E2 (PGE2) on cellular and humoral immunity in the mosquito, An. gambiae. Based on preliminary and previously published studies demonstrating that PGE signaling is an important mediator of cellular immune function, immune priming, and in limiting pathogen survival, here we outline experiments to address the cellular and transcriptional events following PGE2 activation using innovative single-cell and phenomics-based methodologies (Aim 1); the mechanisms of PGE2-mediated immune priming through recently developed genetic tools to promote tissue-specific silencing (Aim 2), and the potential of PGE2 dysregulation to influence pathogen infection outcomes and mosquito fitness by targeting enzymes involved in PGE2 degradation (Aim 3). Therefore, we expect that the outcomes of our proposal will provide an important fundamental insight into the mechanisms of PGE2 regulation, immune cell dynamics, and dysregulation of PGE2-mediated immunity in an emerging model system. We believe these data provide an essential foundation for future studies of mosquito PGE2 signaling and a valuable platform for comparative studies across invertebrate and vertebrate systems. Importantly, the expected outcomes of our proposed experiments also have tremendous potential for translation, where PGE2 dysregulation could serve as a novel target for mosquito control to reduce the heavy burdens of mosquito-borne disease.