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

巴西乳杆菌疫苗抗原和保护中的 T 细胞质量

• 批准号: 8654289
• 负责人: LYNN SOONG
• 金额: $ 7.74万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8654289
• 关键词: Adjuvant; American Leishmaniasis; Animal Model; Antigens; Area; Bacteria; Bioinformatics; Biological Assay; CD4 Positive T Lymphocytes; Cells; Chronic Disease; Clinical; Complex; Cutaneous Leishmaniasis; DNA; Diffuse Cutaneous Leishmaniasis; Disease; Epitopes; Evaluation; Evolution; Failure; Frequencies; Genomics; Goals; Human; Immune response; Immunity; Immunization; In Vitro; Infection; Interferons; Interleukin-2; Knowledge; Leishmania; Leishmaniasis; Life; Lipid A; Memory; Modeling; Molecular; Mouse Strains; Mucocutaneous leishmaniasis; Mus; Nature; Parasites; Pathogenesis; Pharmaceutical Preparations; Proteins; Prunella vulgaris; Public Health; Regimen; Regulation; South America; Staging; System; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; TLR4 gene; TNF gene; Testing; Travel; Tropical Disease; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Virus; antigen L; base; chemotherapy; cytokine; design; empowered; immunogenicity; improved; in vivo; innovation; monophosphoryl lipid A; neglect; novel; pathogen; programs; public health relevance; response; skin lesion; tool; vaccine candidate; vaccine development; vaccine evaluation

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.

描述（由申请人提供）：利什曼病包括广泛的被忽视但重要的热带病；然而，目前还没有针对这种疾病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关于引起保护性t细胞反应和适当调节的寄生虫抗原的信息不足，因为不充分和过度的免疫反应可能有助于发病，导致疫苗失败。我们在动物模型上的研究表明，在亚马逊乳杆菌和巴西乳杆菌感染的初始阶段，分别存在有害和保护性的免疫反应。我们假设合理选择巴西乳杆菌的t细胞抗原接种疫苗，加上适当的佐剂，可以引发广谱和高质量的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中进行检验。目的1将检验通过免疫信息学方法鉴定的巴西利什曼杆菌候选物是否可以交叉保护小鼠免受另一种新世界利什曼原虫感染。前三种候选药物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进行测试，并结合新型TLR4佐剂glucopyranosyl脂质A （GLA）和单磷酰脂质A （MPL）。目标2将检验各种疫苗提供的保护水平与t细胞反应的质量和范围呈正相关的假设。体外和体内试验将用于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。我们将探讨疫苗免疫和化疗诱导的保护的分子基础。本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，并利用这一信息设计这种和其他持续性寄生虫感染的控制策略。本研究的创新之处在于我们对巴西乳杆菌新t细胞抗原的鉴定、t细胞质量和跨种保护评价的综合方法。本研究对合理设计非愈合性利什曼病疫苗具有重要意义，同时也具有一定的指导意义