UV, Neuropeptides, Histamine and Buruli Ulcer Disease

描述(申请人提供)：人类布鲁里溃疡病(BUD)是一种严重的皮肤病，主要由溃疡分枝杆菌(MU)的细胞外感染引起。这种突发的高发病率疾病会导致破坏性的皮肤溃疡，可能会覆盖多达15%的身体表面积。溃疡继发感染极为罕见。有效的治疗需要多次手术切除和植皮，这往往会导致严重的畸形或残疾。无毛豚鼠(GP)感染强毒MU模拟芽孢杆菌。在GP模型中，PI已经表明，感染前暴露于紫外线-B(UV)会加剧芽并抑制对MU的迟发性超敏反应(DTH)。PI还表明，局部感染前暴露于顺式尿囊酸(CUCA)，一种光免疫抑制的起始剂，模拟紫外线对芽的影响。紫外线诱导免疫抑制的一个关键途径是CUCA-神经肽途径。这一途径与紫外线对一般传染病，特别是芽体的影响的相关性尚不清楚。这代表着知识库中的一个严重缺口。因此，这项建议的目的是验证一种假设，即阻断UV-CUCA-神经肽-光免疫抑制通路将阻止紫外线诱导的布鲁里溃疡模型豚鼠MU感染的增强。为了验证我们的假设，将进行两个实验：(1)照射前辣椒素介导的神经肽耗竭是否阻断BUD的紫外线增强？(2)照射前后用降钙素基因相关肽受体拮抗剂、H1和H2组胺拮抗剂或吲哚美辛是否阻断BUD的UV增强？重要的是，将相关对照组纳入拟议的实验将允许检查神经肽-组胺-前列腺素途径在非辐射动物MU感染发病机制中的作用。无论这些实验的结果如何，都将获得关于Bud发病机制的新的和重要的信息。

DESCRIPTION (provided by applicant): Human Buruli ulcer disease (BUD) is a severe skin disease caused by predominantly extracellular infection with Mycobacterium ulcerans (MU). This emergent, high-morbidity disease causes destructive skin ulcers that may cover up to 15% of the body surface area. Secondary infection of the ulcers is extremely rare. Effective treatment requires multiple surgical excisions and skin grafting that often results in significant deformity or disability. Infection of the hairless guinea pig (GP) with virulent MU mimics BUD. The PI has shown that pre-infection exposure to ultraviolet -B (UV) exacerbates BUD and suppresses delayed-type hypersensitivity (DTH) responses to MU in the GP model. The PI has also demonstrated that topical pre- infection exposure to cis-urocanic acid (cUCA), an initiator of photoimmunosuppression, mimics the effects of UV on BUD. A key pathway in UV-induced immunosuppression is the cUCA-neuropeptide pathway. The relevance of this pathway to the effects of UV on infectious disease in general, and BUD in particular, is unknown. This represents a critical gap in the knowledge base. Thus, the aim of this proposal is to test the hypothesis that blocking of the UV-cUCA-neuropeptide-photoimmunosuppression pathway will prevent UV- induced enhancement of MU infection in the hairless guinea pig model of Buruli ulcer disease. To test our hypothesis, 2 experiments will be performed: (1) does pre-irradiation capscaicin-mediated neuropeptide depletion block UV-augmentation of BUD?; and (2) does pre- and post-irradiation treatment with calcitonin gene related peptide receptor antagonists or H1 and H2 histamine antagonists or indomethacin block UV- augmentation of BUD. Importantly, the incorporation of relevant control groups in the proposed experiments will allow for the examination of the role of the neuropeptide-histamine-prostanoid pathway during the pathogenesis of MU infection in non-irradiated animals. Irrespective of the outcomes of these experiments, new and important information on BUD pathogenesis will be obtained.