Abstract Arthropod-borne disease continues to be a significant source of morbidity and mortality worldwide. The ability of an arthropod to harbor and transmit pathogens is termed “vector competency”. Many factors influence vector competency, including how the arthropod immune system responds to the microbe. The intricacies of insect immunity have been well-studied owing the model organism, Drosophila. In contrast, comparatively little is known about tick immunity, representing a fundamental knowledge gap in vector biology. Arthropod immune processes are now increasingly recognized as being divergent across species. For example, we identified a noncanonical Immune Deficiency (IMD) pathway in ticks that limits colonization of two bacterial pathogens: Borrelia burgdorferi (Lyme disease) and Anaplasma phagocytophilum (Human Granulocytic Anaplasmosis). Ticks lack genes encoding upstream IMD pathway regulators. Therefore, the molecular and cellular events preceding the noncanonical IMD pathway in ticks deviate from the classical paradigm defined in insects. We asked in our previously funded R21 whether a specialized stress-response system termed the Unfolded Protein Response (UPR) could impact vector competency through tick immunity. Infection imparts stress on the host and, for this reason, cellular stress-responses are tightly intertwined with innate immunity. Our data shows that the UPR is induced by tick-borne bacteria and initiates the noncanonical IMD pathway in ticks. Through RNAi knockdown and pharmacological manipulation, we show that the IRE1α branch of the UPR signals through the adapter molecule TRAF2 to restrict vector colonization by A. phagocytophilum and B. burgdorferi both in vitro and in vivo. Collectively, our findings provide an explanation for how the core IMD pathway is activated independent of canonical upstream regulators. Based on these findings, our central hypothesis is that the UPR functionally regulates vector-microbe interactions through crosstalk with the IMD pathway. AIM 1 of this proposal will now investigate the role of the I. scapularis UPR on microbial growth, migration kinetics through tick tissues and/or transmission to a naïve host. AIM 2 will uncover the mechanistic linkage between the UPR and the noncanonical IMD pathway using an unbiased approach to define and characterize the signalosome during infection. Since microbial infections impart stress on host systems and cellular stress responses are well conserved across eukaryotes, we expect that the findings from this R01 will uncover novel determinants of vector competence and may have broad relevance to many arthropod-pathogen systems.