CD4+ T cell dysfunction during visceral leishmaniasis

内脏利什曼病期间 CD4 T 细胞功能障碍

• 批准号: 10571460
• 负责人: Jeffrey C. Nolz
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571460
• 关键词: Acceleration; Adaptive Immune System; Animals; Antigens; Bacterial Infections; Biological Models; CD4 Positive T Lymphocytes; CTLA4 gene; Cause of Death; Cell physiology; Cellular Immunity; Cessation of life; Chronic; Complex; Cutaneous; Cutaneous Leishmaniasis; Data; Development; Disease; Epitopes; Experimental Models; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Glycosome; Goals; Human; Immunity; Immunization; Immunize; Immunotherapy; Infection; Inflammatory; Interleukin-10; Kinetics; Left; Leishmania; Leishmania donovani; Leishmaniasis; Liver; Longevity; Macrophage; Mediating; Molecular; Molecular Profiling; Multiple Organ Failure; Mus; Parasites; Parasitic Diseases; Parasitic infection; Phenotype; Phosphoenolpyruvate Carboxylase; Production; Reporter; Research; Signal Pathway; Spleen; Systemic disease; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; Vaccinia virus; Viral; Viral Cancer; Virus Diseases; Visceral; Visceral Leishmaniasis; chronic infection; cytokine; cytotoxic CD8 T cells; exhaust; exhaustion; functional restoration; gene network; improved; memory CD4 T lymphocyte; mouse model; neglected tropical diseases; neutralizing antibody; pathogen; prevent; programmed cell death protein 1; receptor; response; skin disorder; therapeutic immunization; treatment strategy; vaccine development; vaccinia virus vector

PROJECT SUMMARY/ABSTRACT Visceral leishmaniasis is a devastating, neglected tropical disease, ultimately leading to multiorgan failure and death when left untreated. As with many parasitic infections, efforts to develop an effective vaccine have remained unsuccessful. In contrast to a number of infectious pathogens which can be controlled by neutralizing antibodies and/or cytotoxic CD8+ T cells, protection against leishmaniasis is largely mediated by T helper 1 differentiated CD4+ T cells, but how CD4+ T cell activation, differentiation, and function are regulated during visceral leishmaniasis is still largely unknown. A major limitation to these studies has been the inability to accurately identify Leishmania-specific CD4+ T cells in experimental model systems in order to assess T cell longevity and functions during and after the course of the infection. Here, using a recently identified MHC-II epitope conserved across Leishmania species, we show that in contrast to cutaneous versions of leishmaniasis, antigen-specific CD4+ T cells become functionally exhausted during visceral leishmaniasis, produce IL-10, and express high levels of the inhibitory receptors PD-1 and CTLA-4. This suggests that rather than remaining “hidden”, high parasite burden and/or antigen load overwhelms the adaptive immune system to the point where antigen-specific CD4+ T cells lose the capacity to produce the necessary pro-inflammatory cytokines to kill parasites residing within macrophages. Because there is currently no effective vaccine and limited treatment options for leishmaniasis, we have generated recombinant Vaccinia virus (VacV) vectors expressing the immunodominant Leishmania epitope targeted for MHC-II presentation to study the CD4+ T cell response against this parasitic infection. To begin to investigate the mechanisms of CD4+ T cell activation and to identify strategies to reverse or limit T cell dysfunction during visceral leishmaniasis, we will 1) define the functions and gene expression profiles of antigen-specific CD4+ T cells that become activated following either cutaneous or visceral Leishmania infections and 2) determine if therapeutic viral immunization combined with immunotherapy restores function to CD4+ T cells during visceral leishmaniasis. The overall goal of this project will be to begin to define the mechanisms that regulate CD4+ T cell function and dysfunction during visceral leishmaniasis, which will contribute to our long-term goal of improving vaccine design and therapies against this complex parasite.

项目摘要/摘要 内脏利什曼病是一种毁灭性的、被忽视的热带疾病，最终导致多器官衰竭和 如果不治疗就会死亡。与许多寄生虫感染一样，开发有效疫苗的努力已经 仍然没有成功。与一些可通过中和控制的感染性病原体相比 抗体和/或细胞毒性CD8+T细胞对利什曼病的保护作用在很大程度上是由T辅助分子1介导的 分化的CD4+T细胞，但如何调节CD4+T细胞的激活、分化和功能 内脏利什曼病在很大程度上仍是未知的。这些研究的一个主要限制是无法 在实验模型系统中准确识别利什曼原虫特异性的CD4+T细胞，以便评估T细胞 在感染过程中和之后的寿命和功能。在这里，使用最近发现的MHC-II 在利什曼原虫物种中保存的表位，我们表明，与皮肤版本的利什曼原虫相比， 在内脏利什曼病期间，抗原特异性的CD4+T细胞功能衰竭，产生IL-10，并 高水平表达抑制受体PD-1和CTLA-4。这表明，与其继续 “隐藏”、高寄生虫负担和/或抗原负荷使适应性免疫系统不堪重负 抗原特异性的CD4+T细胞失去产生必要的促炎细胞因子的能力以杀死 寄生在巨噬细胞内的寄生虫。因为目前还没有有效的疫苗和有限的治疗方法 利什曼病的选择，我们已经产生了重组痘苗病毒(VacV)表达载体 以MHC-II为靶点的免疫优势利什曼原虫表位研究CD4+T细胞对 这种寄生虫感染。开始研究CD4+T细胞活化的机制并找出策略 为了逆转或限制内脏利什曼病的T细胞功能障碍，我们将1)定义功能和基因 经皮肤或内脏激活的抗原特异性CD4+T细胞的表达谱 利什曼原虫感染和2)确定治疗性病毒免疫联合免疫治疗是否恢复 内脏利什曼病对CD4+T细胞功能的影响该项目的总体目标将是开始定义 内脏利什曼病时调节CD4+T细胞功能和功能障碍的机制 为我们改进针对这种复杂寄生虫的疫苗设计和治疗的长期目标做出贡献。