Ixodes scapularis Immuno-Developmental and Metabolic Signaling Pathways and Interference with Ticks and Tick-borne Pathogens

OVERALL – Abstract The proposed renewal Program Project (P01), entitled “Ixodes scapularis Immuno-Developmental and Metabolic Signaling Pathways and Interference with Ticks and Tick-borne Pathogens”, aims to understand the molecular mechanisms by which a set of newly recognized I. scapularis conserved signaling pathways, either discretely or via synergism, govern key episodes of arthropod development, metabolism, and immunobiology that shape their vectorial competence for the harboring and transmission of agents of Lyme disease and anaplasmosis. We have discovered unorthodox aspects of tick signaling pathways that involve mammalian-arthropodal crosstalk and are triggered by ingested cytokines, scavenger receptor-like proteins, or hormones, and influence tick microbicidal responses, development, and/or metabolism, as exemplified by the Dome1-JAK-STAT, immune deficiency (IMD), and adiponectin receptor-like protein (ISARL) signaling pathways. We have also established that suppressing the expression of select key extracellular components of these signaling pathways, such as via RNA interference-mediated knockdown of cell surface tick receptors or extracellular molecules, interrupts tick engorgement or pathogen transmission. In this renewal application, which builds on these paradigms and combines the complementary expertise and resources from four institutions with impressive histories of research involving tick-borne infections, we propose to further characterize these signaling pathways and explore whether essential cell surface tick receptors, domains, and/or extracellular molecules could be targeted as novel anti-tick vaccines to impede essential aspects of vector biology and tick-pathogen life cycles. Two of the most widespread and emerging bacterial pathogens, Borrelia burgdorferi and Anaplasma phagocytophilum, remain our focus as prototypic examples of tick- transmitted extracellular and intracellular microbes, respectively. This renewal Program Project Grant leverages specific assays, tools, and methodologies developed by our laboratories, supported by an Administrative Core and Tick Resources Core, whereby new information as well as organisms, cell lines, and resources will be generated and shared, not only among the P01 team, but also with broader scientific communities via open-source databases, platforms, and the project website. The proposed goals are to: 1) Operate Resource Cores that provide research reagents and information to all Projects and the scientific community; 2) Characterize signaling pathways regulating vector immune-developmental cascades; 3) Investigate metabolic pathways regulating tick immune responses; and 4) Explore tick immune-developmental and metabolic pathways as anti-tick vaccine targets. Altogether, this proposal will increase our understanding of atypical tick biology and advance the development of new preventions against major tick-borne infections, while also planting new seeds of innovative research in vector-borne infections and enticing a new generation of scientists to engage in and advance this important yet neglected field of scientific research.