A cross-species signaling system in tick immunity and development

Borrelia burgdorferi (Bb), the pathogen of Lyme disease, cycles between mammals and ticks belonging to the Ixodes scapularis species. During a tick’s bloodmeal engorgement on an infected host, Bb can enter ticks and colonize the gut tissues. In our efforts to explore how ticks respond to invading Bb in the blood meal, we discovered a cross-species communication pathway that enables I. scapularis to sense mammalian-derived factors, such as the interferon-γ cytokine, that are ingested in the tick’s blood meal, which then bind a tick cell surface receptor, subsequently triggering the tick JAK-STAT pathway. Once activated, this Dome1–JAK–STAT signaling system not only enhances tick microbicidal responses against invading pathogens like Bb by upregulating two antimicrobial proteins, a CLIP domain serine protease annotated as SP10 and a domesticated amidase effector called Dae2, but also facilitates tick hematophagy and development. However, despite our initial discovery, the mechanistic details of how this newly discovered pathway dually influence vector immunity and development are missing, which constitute the focus of our current application. The role of Dome1 in activating the JAK–STAT pathway is evident even in the absence of IFNγ or Bb infection, suggesting that endogenous tick ligand(s) could bind and activate the pathway. In fact, our preliminary data now identify a novel tick protein that acts as the native Dome1 ligand, termed herein as the I. scapularis Dome1 ligand (IscDl). Dome1 is a multidomain protein with structural similarity to the vertebrate class I cytokine receptors, which can act as "shared" receptors, recruiting multiple cytokines and mediating a wide range of functions. Therefore, our first aim will define how IscDl-Dome1 interactions, individually or cooperatively with the mammalian ligand (IFNγ), impact tick immune-developmental events. The cross-species Dome1–JAK–STAT pathway specifically employs a Rho GTPase (called IGTPase) to severely limit Bb levels in ticks via the induction of antimicrobial proteins SP10 and Dae2 via undefined mechanisms. Based on our extensive new preliminary data, our second aim seeks to investigate the molecular mechanisms of how these antimicrobial proteins individually or synergistically kill B. burgdorferi, limiting bacterial persistence in vivo. We also seek to investigate the mechanisms of how the STAT–IGTPase cascade exerts regulations of SP10 and Dae2. Altogether, our study will provide new insights into the cross-species I. scapularis signaling cascade, focusing on one of the first identified arthropod signal transducers with shared cytokines, as well as immune-effector mechanisms with anti-Bb activities and their regulation, potentially contributing to the future development of new interventions against tick-borne infections like Lyme disease. Project Number: 1R01AI194433-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: UTPAL PAL | Institution: UNIV OF MARYLAND, COLLEGE PARK, COLLEGE PARK, MD | Award Amount: $518,099 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-M (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19443301