Cutaneous Contact Hypersensitivity - A Surrogate Model for Tick-Immunity

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P/F #61 - "Cutaneous contact hypersensitivity-a surrogate model for tick-immunity" Sukanya Narasimhan, PhD (Rheumatology), Fred Kantor, MD (Allergy), Erol Fikrig, MD (Infectious Disease), Christine Ko, MD (Dermatology) Eligibility Category: Established investigator with no previous work in skin diseases Abstract: This proposal will focus on Ixodes scapularis ticks that vector bacterial and protozaoan pathogens including Borrelia burgdorferi, the agent of Lyme disease. Ticks feed on mammalian hosts for 4-6 days to acquire a blood-meal and to do so they tear through the dermis and feed from the hematoma that forms at the bite-site. This cutaneous lesion is the site of entry and exit of pathogens from the host or from the tick. The cutaneous immune responses triggered by tick feeding is a critical interface between the tick, the host and the pathogen and determines the success of tick feeding and pathogen transmission or acquisition. Ticks secrete salivary components that thwart host haemostasis and inflammatory responses to facilitate feeding and the pathogens perhaps exploit these tick salivary components for their own survival. Ticks can repeatedly feed on mice, their natural host, without eliciting any resistance to tick feeding. Interestingly, on animals such as guinea pigs and rabbits that do not serve as natural hosts, tick salivary components provoke an immune response upon repeated tick infestations characterized predominantly by cutaneous basophil hypersensitivity (CBH). Guinea pigs have served as a classic model of acquired tick-immunity and studies conducted in the last several decades have demonstrated that the increased recruitment of basophils to the tick-feeding site followed by their degranulation mediates tick rejection. It is also not understood why mice do not develop immunity to I. scapularis ticks unlike guinea pigs. We posit that tick salivary proteins interact with mouse immune cells to successfully thwart recruitment of inflammatory cells detrimental to tick feeding. We also hypothesize that this activity might be enabled by tick salivary proteins specifically induced while feeding on mice and not on guinea pigs. To test these postulates a mouse model of cutaneous contact hypersensitivity, characterized by recruitment of basophils and mast cells to the skin site that is sensitized to the specific hapten , will be exploited. In this proposal we will first determine if ticks successfully modulate cutaneous contact hypersensitivity induced by hapten sensitization in mice. We will then temporally dissect tick salivary components critical to modulate cutaneous hypersensitivity and determine if the ticks fed on mice and ticks fed on guinea pigs elaborate different salivary proteins. This pilot study will demonstrate the utility of a murine model of cutaneous hypersensitivity as a surrogate in vivo model of tick-immunity. In keeping with the stated funding priorities of the YSDRC P/F Program, each of the four new P/F projects involve multidisiciplinary collaborative associations. Collectively, the 4 projects (three new, one 2nd year renewal project) involve the participation of 10 investigators (including three investigators not previously affiliated with the YSDRCC) representing 6 different departments at Yale. Each of the P/F project P.l.s qualified for P/F funding by virtue of established investigators, either with no previous work in cutaneous biology/pathology (one investigator) or with new project that represents a significant departure or new initiative compared with previous skin-related research activities. . Four of the new P/Fs are in one of the YSDRC's two principal arenas of research focus, namely, Cutaneous Immunobiology/ Immunopathology/ Vaccine Development, while two other center around the second YSDRC thematic research arena of Epidermal Biology.