Abstract Arthropod immunity is a key factor influencing vector competence. We recently identified an atypical Immune Deficiency (IMD) pathway in Ixodes scapularis ticks that responds to and restricts Borrelia burgdorferi (Lyme disease) and Anaplasma phagocytophilum (Human Granulocytic Anaplasmosis). Host cell stress-responses are closely intertwined with immunity and can function to either potentiate or antagonize immune signaling. Whether stress-response pathways intersect with arthropod immunity to influence vector competence remains unknown. Stress Granules (SGs) are aggregates of RNA and protein that transiently form in the cytoplasm of stressed cells, such as during infection. SG formation is highly conserved throughout eukaryotes and has known immune regulatory roles in mammals. Once formed, SGs become cell signaling hubs that can intercept molecules from other pathways to modulate cellular processes. For instance, SGs can inhibit the mammalian analogue to the IMD pathway, the Tumor Necrosis Factor Receptor (TNFR) network, by sequestering signaling proteins away from immune complexes. SGs are induced when eIF2α (eukaryotic translation initiation factor 2α) is phosphorylated by stress-sensing kinases, such as PERK (protein kinase R-like endoplasmic reticulum kinase). In this R21 application, we report that PERK-eIF2α signaling promotes A. phagocytophilum colonization and replication in tick cells. This observation together with known immune inhibitory roles of eIF2α-induced SGs prompted us to look for SG formation in ticks. We found 13 SG-assembly genes that are induced in the salivary glands and/or midguts of A. phagocytophilum-infected ticks. Accordingly, our central hypothesis is that PERK- eIF2α-induced SGs antagonize immune signaling in ticks, which promotes bacterial pathogen colonization. AIM 1 of this proposal will evaluate whether bacterial infection induces SGs in tick cells using immunofluorescent microscopy, protein biochemistry and pharmacological inhibition. AIM 2 will assess the impact of SGs on bacterial colonization and tick immunity in vitro using transcriptional knockdown and pharmacological modulators. AIM 3 will investigate whether SG machinery influences pathogen colonization and maintenance in vivo by using transcriptional knockdown in larvae followed by A. phagocytophilum or B. burgdorferi challenge. As SG formation is a conserved evolutionary mechanism, investigating this phenomenon as it relates to arthropod immunity and vector competence will provide novel insights for the broader vector biology community.