L. Brazilensis Vaccine Antigens and T-cell Quality in Protection

描述(申请人提供)：利什曼病包括一系列被忽视但重要的热带疾病；但目前还没有针对任何临床形式的有效疫苗。开发有效的抗利什曼原虫疫苗的主要障碍是缺乏关于寄生虫抗原的信息，这些抗原可以引起保护性T细胞反应和适当的调节，因为不足和过度的免疫反应可能导致发病，导致疫苗失败。我们在动物模型中的研究表明，在感染亚马孙乳杆菌和巴西乳杆菌的初始阶段，分别编程的有害和保护性免疫反应。我们推测，用合理选择的巴西利什曼原虫T细胞抗原和适当的佐剂免疫，可以诱导出广谱和高质量的T细胞免疫，以控制美国皮肤利什曼病。这一假设将在两个具体目标上得到检验。目的1将检查通过免疫信息学方法确定的候选巴西利什曼原虫是否能够交叉保护小鼠免受另一种新世界利什曼原虫感染。前三名候选疫苗的免疫原性和疫苗潜力将通过基于DNA和蛋白质的免疫方案以及新型TLR4佐剂葡萄糖吡喃糖脂A(GLA)和单磷脂A(MPL)进行测试。目标2将检验各种疫苗提供的保护水平与T细胞反应的质量和光谱正相关的假设。体外和体内实验将被用来分析免疫和寄生虫攻击过程中多功能CD4+T效应细胞和记忆细胞的频率。我们将研究疫苗免疫和化疗诱导保护的分子基础。这项研究的长期目标是确定与利什曼原虫感染相关的保护机制，并利用这些信息设计针对这种和其他持续寄生虫感染的控制策略。本研究的创新之处在于，我们采用了一种综合的方法来鉴定巴西钩端螺旋体新的T细胞抗原，并评估T细胞质量和跨物种保护。这项研究对设计合理的非愈合性利什曼病疫苗具有很高的相关性，但也有 对其他由细胞内病原体引起的慢性疾病的广泛影响。

DESCRIPTION (provided by applicant): Leishmaniasis encompasses a broad spectrum of neglected, but important tropical diseases; yet there are no effective vaccines for any clinical forms of the disease. The major obstacle in developing an effective anti- Leishmania vaccine is insufficient information on parasite antigens that elicit protective T-cell responses and appropriate regulation, since inadequate and excessive immune responses can contribute to pathogenesis, leading to vaccine failure. Our studies in animal models have revealed detrimental and protective immune responses programmed at the initial stages of infections with L. amazonensis and L. braziliensis, respectively. We hypothesized that vaccination with rationally selected T-cell antigens of L. braziliensis, together with appropriate adjuvants, can elicit a broad-spectrum and high-quality T-cell immunity for the control of American cutaneous leishmaniasis. This hypothesis will be tested in two Specific Aims. Aim 1 will examine whether L. braziliensis candidates identified through an immunoinformatics approach can cross-protect mice against another New World Leishmania spp infection. The immunogenicity and vaccine potential of the top three candidates will be tested via DNA- and protein-based immunization regimens, in conjunction with novel TLR4- adjuvants glucopyranosyl lipid A (GLA) and monophosphoryl lipid A (MPL). Aim 2 will test the hypothesis that the level of protection offered by various vaccines positively correlates with the quality and spectrum of T-cell responses. In vitro and in vivo assays will be used to analyze the frequency of multi-functional CD4+ T effector and memory cells during immunization and parasite challenge. We will examine the molecular basis of protection induced by vaccine immunization and chemotherapy. The long-term goal of this study is to define the protective mechanisms associated with Leishmania infection and to utilize this information for the design of control strategies for this and other persistent parasitc infections. The innovation of this study is our comprehensive approaches for identifying new T-cell antigens of L. braziliensis and evaluating T-cell quality and cross-species protection. This study is highly relevant to the rational vaccine design for non-healing leishmaniasis, but also has broad implications for other chronic diseases caused by intracellular pathogens.