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 diseasesAbstract: This proposal will focus on Ixodes scapularis ticks that vector bacterial and protozaoan pathogensincluding Borrelia burgdorferi, the agent of Lyme disease. Ticks feed on mammalian hosts for 4-6 days toacquire a blood-meal and to do so they tear through the dermis and feed from the hematoma that forms at thebite-site. This cutaneous lesion is the site of entry and exit of pathogens from the host or from the tick. Thecutaneous immune responses triggered by tick feeding is a critical interface between the tick, the host and thepathogen and determines the success of tick feeding and pathogen transmission or acquisition. Ticks secretesalivary components that thwart host haemostasis and inflammatory responses to facilitate feeding and thepathogens perhaps exploit these tick salivary components for their own survival. Ticks can repeatedly feed onmice, their natural host, without eliciting any resistance to tick feeding. Interestingly, on animals such asguinea pigs and rabbits that do not serve as natural hosts, tick salivary components provoke an immuneresponse 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 lastseveral decades have demonstrated that the increased recruitment of basophils to the tick-feeding sitefollowed by their degranulation mediates tick rejection. It is also not understood why mice do not developimmunity to I. scapularis ticks unlike guinea pigs. We posit that tick salivary proteins interact with mouseimmune cells to successfully thwart recruitment of inflammatory cells detrimental to tick feeding. We alsohypothesize that this activity might be enabled by tick salivary proteins specifically induced while feeding onmice 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 contacthypersensitivity induced by hapten sensitization in mice. We will then temporally dissect tick salivarycomponents critical to modulate cutaneous hypersensitivity and determine if the ticks fed on mice and ticks fedon guinea pigs elaborate different salivary proteins. This pilot study will demonstrate the utility of a murinemodel 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 projectsinvolve multidisiciplinary collaborative associations. Collectively, the 4 projects (three new, one 2ndyear renewal project) involve the participation of 10 investigators (including three investigators notpreviously affiliated with the YSDRCC) representing 6 different departments at Yale. Each of the P/Fproject P.l.s qualified for P/F funding by virtue of established investigators, either with no previous work incutaneous biology/pathology (one investigator) or with new project that represents a significant departure ornew initiative compared with previous skin-related research activities. . Four of the new P/Fs are in one of theYSDRC's two principal arenas of research focus, namely, Cutaneous Immunobiology/ Immunopathology/Vaccine Development, while two other center around the second YSDRC thematic research arena ofEpidermal Biology.
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