Cutaneous Contact Hypersensitivity - A Surrogate Model for Tick-Immunity

P/F #61 -“皮肤接触性超敏反应-蜱免疫的替代模型” Sukanya Narasimhan，博士（流变学），Fred Kantor，医学博士（过敏），Erol Fikrig，医学博士（传染病）， 克莉丝汀高，医学博士（皮肤科） 资格类别：已确立的研究者，以前没有皮肤病方面的工作 翻译后摘要：这项建议将集中在肩突硬蜱，载体细菌和原生动物病原体 包括莱姆病病原体伯氏疏螺旋体蜱虫以哺乳动物宿主为食4-6天， 获得血餐，这样做，他们通过皮肤和饲料的血肿，形成在 咬痕这种皮肤病变是病原体从宿主或蜱虫进入和离开的部位。的 由蜱虫取食引发的皮肤免疫反应是蜱虫、宿主和宿主之间的关键界面。 病原体，并决定蜱虫喂养和病原体传播或获取的成功。蜱分泌 唾液成分，阻碍宿主止血和炎症反应，以促进进食， 病原体可能利用这些蜱的唾液成分来维持自身的生存。蜱虫可以反复以 小鼠，它们的天然宿主，而不会引起任何对蜱虫喂养的抵抗。有趣的是，在动物身上， 豚鼠和兔子不作为自然宿主，蜱唾液成分激发免疫 对以皮肤嗜碱性粒细胞超敏反应为主要特征的反复蜱虫感染的反应 （CBH）.豚鼠是获得性蜱免疫的经典模型， 几十年的研究表明，嗜碱性粒细胞在蜱虫取食部位的增加， 随后它们的脱粒介导蜱排斥。也不明白为什么老鼠不发育 免疫力I。肩胛蜱不像豚鼠。我们证实蜱唾液蛋白与小鼠相互作用 免疫细胞成功地阻止了对蜱虫进食有害的炎性细胞的募集。我们也 假设这种活性可能是由蜱唾液蛋白特异性诱导， 小鼠而不是豚鼠。为了测试这些假设，建立了皮肤接触性超敏反应的小鼠模型， 其特征在于嗜碱性粒细胞和肥大细胞聚集到对特异性半抗原敏感的皮肤部位 ，将被利用。在这个建议中，我们将首先确定蜱是否成功地调节皮肤接触 在小鼠中通过半抗原致敏诱导的超敏反应。然后我们将暂时解剖蜱唾液 调节皮肤超敏反应的关键成分，并确定蜱虫是否以小鼠为食， 在豚鼠身上产生了不同的唾液蛋白。这项初步研究将证明一种小鼠 皮肤超敏反应模型作为蜱免疫的替代体内模型。 为配合青年发展资源中心规划及设施计划的既定拨款优先次序， 涉及多学科协作协会。总的来说，这4个项目（三个新项目，一个第二项目， 10名调查员（包括3名不具备 以前隶属于YSDRCC）代表耶鲁大学6个不同的部门。每个P/F 项目P.l.s有资格获得P/F资金，因为已经确定了调查人员，或者以前没有工作， 皮肤生物学/病理学（一名研究者）或代表重大偏离的新项目，或 与以前的皮肤相关研究活动相比，这是一项新举措。.四个新的P/F在其中一个 YSDRC的两个主要研究领域，即皮肤免疫生物学/免疫病理学/ 疫苗开发，而其他两个中心围绕第二YSDRC专题研究竞技场的 表皮生物学。

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.