Dome1–JAK–STAT signaling between parasite and host integrates vector immunity and development

Ancestral signaling pathways serve critical roles in metazoan development, physiology, and immunity. We report an evolutionary interspecies communication pathway involving a central Ixodes scapularis tick receptor termed Dome1, which acquired a mammalian cytokine receptor motif exhibiting high affinity for interferon-gamma (IFN-γ). Host-derived IFN-γ facilitates Dome1-mediated activation of the Ixodes JAK–STAT pathway. This accelerates tick blood meal acquisition and development while upregulating antimicrobial components. The Dome1–JAK–STAT pathway, which exists in most Ixodid tick genomes, regulates the regeneration and proliferation of gut cells—including stem cells—and dictates metamorphosis through the Hedgehog and Notch–Delta networks, ultimately affecting Ixodes vectorial competence. We highlight the evolutionary dependence of I. scapularis on mammalian hosts through cross-species signaling mechanisms that dually influence arthropod immunity and development. Description Ticks repurpose host IFN-γ to Dome-inate Many arthropods use cytokine-like molecules such as Unpaired (UPD) to activate JAK–STAT signaling and drive robust antibacterial responses. Curiously, deer ticks (Ixodes scapularis), which serve as a vector for Lyme disease, lack identifiable UPD homologs. Rana et al. found instead in I. scapularis a receptor called Dome1 that binds to and is activated by mammalian interferon-γ ingested in the tick’s blood meal. Dome1, which triggers the JAK–STAT pathway, not only enhances tick immunity but is also crucial for tick metamorphosis and organ development. Thus, deer ticks have successfully coopted mammalian host immune signaling for their own ends using pathways that could potentially be targeted in future ectoparasite control strategies. —STS Parasitic ticks exploit host-derived interferon-γ through cross-species signaling to promote arthropod immunity and development. INTRODUCTION Ticks have evolved into a monophyletic group of highly adapted blood-feeding ectoparasites that originated from a clade of free-living scavenger mites nearly 225 million years ago. Unlike most geographically confined tick species that prefer a single vertebrate host, Ixodes spp. can parasitize many vertebrates and transmit diverse pathogens. Ixodid ticks undergo only three feeding events during their multiyear lifespan, ingesting blood meals that are nearly 100 times their weight. Their characteristic physiological adaptations were likely shaped by their sophisticated hematophagy and associations with coevolving vertebrate hosts. The molecular basis of how ticks maintain their complex postembryonic developmental program as well as their vectorial competence remains unclear. Ticks contain a functional JAK–STAT signaling cascade that induces robust antibacterial responses capable of limiting the proliferation of tick-borne pathogens. The pathway is activated in many arthropods by cytokine-like molecules such as Unpaired (UPD). However, the Ixodes scapularis genome is unusually devoid of recognizable UPD orthologs. RATIONALE We recently discovered a cross-species cell signaling pathway in which a mammalian interferon (IFN-γ) ingested with the tick blood meal activates the Ixodes JAK–STAT pathway, generating potent microbicidal activities within the vector. To further elucidate a parallel interferon-like defense system in ticks, we have explored the identity and characteristics of the tick receptor for IFN-γ to uncover the mechanisms and biological significance of a cross-species cell signaling cascade that extends from mammals to their ectoparasites. RESULTS We identified an I. scapularis receptor, Dome1, which binds with high selectivity and affinity to vertebrate (mouse, human, and avian) IFN-γ. Unlike Dome orthologs in other arthropods, including non-Ixodes ticks, Dome1 features unique extracellular regions found in vertebrate cytokine receptors. Dome1 colocalizes with IFN-γ on the luminal surface of the tick gut epithelium. The receptor is induced by ingested IFN-γ and regulates microbicidal responses orchestrated by the JAK–STAT pathway. Unexpectedly, Dome1 not only augmented tick immune responses, but was also required for I. scapularis development. Systemic Dome1 knockdown persisted from subadult to female I. scapularis and their offspring, and severely impaired tick fecundity and postembryonic development, reflected by failure to molt, loss of bilateral symmetry, and malformed internal organs and appendages, including missing legs, mouthparts, and anal pore structures. The Dome1–JAK–STAT pathway, present in most Ixodid tick genomes, directed the maintenance of the gut proteome and microbiome, in addition to supporting the regeneration and proliferation of gut cells, including stem cells. Dome1–JAK–STAT signaling dictated tick metamorphosis and organ development through the Hedgehog and Notch–Delta biochemical networks, ultimately impacting the ability of Ixodes to transmit Borrelia burgdorferi, the Lyme disease pathogen, to naïve murine hosts. CONCLUSION We identify how certain conserved metazoan cell signaling pathways flexibly adapt vertebrate IFN-γ for use in arthropod immunity and development through the Dome1 receptor. Our studies highlight the evolutionary dependence of the major blood-feeding arthropod I. scapularis on mammalian hosts through cross-species signaling mechanisms that extend from mammals to their ectoparasites and influence arthropod immunity, vectorial competence, and development. Mammalian-arthropodal crosstalk integrates vector immunity and development. The Ixodes scapularis protein Dome1 recruits mammalian IFN-γ from the tick’s blood meal. The interaction activates the tick JAK–STAT pathway, triggering signaling intermediaries, including an antimicrobial protein and Hedgehog protein, which affects tick metamorphosis, gut homeostasis, and pathogen transmission. Knockdowns of pathway components highlight the biological significance of cross-species signaling between mammals and their ectoparasites, which converge to regulate both arthropod immunity and development.