Metabolic Pathways Regulating Tick Immune Responses

PROJECT 2 - Summary/Abstract: Ticks possess an intimate relationship with their mammalian hosts. Through evolution, ticks gained unique physiological adaptations that allowed prolonged blood-feeding and tolerance to microbes that are pathogenic to humans. Tick-borne microbes must overcome barriers imposed by the arthropod immune system while avoiding detriment to the vector. Additionally, they may co-opt vector pathways to ensure colonization. These interspecies relationships rely on metabolism and must be tightly regulated to avoid fitness costs. Recently, this P01 team identified several tick pathways that are activated by host- or infection-derived molecules that integrate arthropod immunity and metabolism. For instance, the Pedra laboratory determined that a CD36 homolog binds infection-derived lipids and elicits activation of the tick IMD [Immune Deficiency] pathway, while simultaneously regulating ecdysteroid biosynthesis and molting. Additionally, the Pal and the Fikrig laboratories uncovered that ticks sense mammalian host-derived molecules in the blood meal through immune [Dome-Jak/ STAT (Janus kinase signal transducer and activator of transcription] and hormonal [ISARL (Ixodes scapularis Adiponectin Receptor-like Protein/Adiponectin] signaling networks, which influences glucose and lipid metabolism in addition to ecdysis. Although mechanisms of immunometabolism have been studied in insects and mammals, the connection between the immune system and metabolism in ticks remain ill-defined. For this competing renewal project, we will build on earlier findings and investigate the nexus between immunity, metabolism, and ecdysis in ticks. The central hypothesis for Project 2 in this P01 application is that the immune response against microbes is intertwined with metabolism to preserve organismal homeostasis in ticks. In Aim #1 of this proposal, we will assess how the IMD, Dome-JAK/STAT, and ISARL/adiponectin pathways regulate metabolism on both cellular and organismal level. Using a multi-omics approach, we will determine how immune signaling affects metabolic pathways during microbial colonization. In Aim #2 of this proposal, we will investigate how the metabolic state of I. scapularis affects immune signaling, fitness, and bacterial acquisition and transmission. Altogether, this project will address the emerging concept that immunity and metabolism operate within a physiological framework in ticks.