Signaling Pathways Regulating Vector Immune-Developmental Cascades

Univ Of Maryland, College Park, College Park MD

Investigators

Linked publications & trials

Abstract

PROJECT 1 - Abstract The Project 1 studies seek to uncover the mechanistic details of how select tick signaling pathways govern immune-developmental cascades in Ixodes scapularis ticks and their vectorial competence, impacting the transmission of two major tick-borne pathogens – the agents of Lyme disease and anaplasmosis. Using I. scapularis as a model, a major goal is to identify extracellular signaling components as targets of anti-tick vaccines that interfere with the transmission of major tick-borne infections prevalent in the United States and elsewhere. Due to their remarkable evolutionary divergence from other arthropods, unique lifestyles, and wide geographical and host ranges, Ixodes ticks have evolved unorthodox traits in their utilization of conserved metazoan cell signaling systems. In our recent collaborative work supported by the original P01, we discovered multiple novel cross-species signaling cascades that enable I. scapularis ticks to sense mammalian-derived factors, such as the interferon-γ (IFNγ) cytokine or adiponectin hormone, that are ingested in the tick’s blood meal, which then bind target tick cell surface receptors and trigger specific signaling cascades, as we have discovered for the Dome1-JAK-STAT or adiponectin receptor-like protein (ISARL) signaling pathways. Once activated, these cross-kingdom signaling systems not only enhance tick microbicidal responses against invading pathogens, but also facilitate multiple aspects of tick biology, including hematophagy, metamorphosis, and organ development, ultimately shaping their vectorial competence. We also discovered that conventional and intrinsic tick immune signaling hubs, such as the immune deficiency (IMD) pathway, regulate microbicidal immune responses, in addition to governing specific aspects of tick development and metabolism, also impacting tick vectorial competence. Synergizing with the other studies detailed in the scientific Projects and Tick Resources Core of this P01 renewal proposal, we will determine how Dome1-JAK-STAT (Aim 1) or other pathways, such as ISARL and IMD (Aim 2), integrate and regulate immune- developmental events. We hypothesize that these pathways may be interconnected and that they, either discreetly or synergistically, affect specific aspects of tick immunity and development, thereby impacting the transmission of major tick-borne bacterial pathogens. Given that these signaling component or specific domains are conserved across major Ixodid ticks of public health importance, we will study the biological significance of select extracellular components of these key pathways, such as cell surface receptors or their tick-specific domains/regions, that are essential for signaling functions, justifying their roles as targets for novel anti-tick vaccines. Altogether, these studies will uncover atypical aspects of tick biology, immunity, and development, and their relationship with other tick biological events, such as tick metabolism and physiology, contributing to the development of new interventions against tick-borne infections.