Mechanistic investigation of differential T cell responses to distinct Mycobacterium tuberculosis antigens

T 细胞对不同结核分枝杆菌抗原的差异反应的机制研究

基本信息

  • 批准号:
    10721879
  • 负责人:
  • 金额:
    $ 4.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Abstract Tuberculosis (TB) is a major global health threat and the only licensed TB vaccine, Bacille Calmette-Guérin (BCG), is inadequate: despite widespread use of BCG, there were 9.9 million new TB cases globally in 2020. Thus, improved vaccines against Mtb are urgently needed. T cell responses remain the primary goal of TB vaccines, as CD4 T cells are necessary to control Mtb in humans and animal models. T cell vaccines have been thus far unsuccessful in preventing infection, but the recent clinical trial of M72-AS01E demonstrated ~50% efficacy as a Prevention of Disease (POD) vaccine. Since TB is transmitted by those with active disease, which is characterized by inflammation and immunopathology, a vaccine that reduces or prevents active disease and immunopathology can have a large impact on the global problem of TB. However, the most optimal antigen target(s) for TB vaccines are not defined, and the lack of evolutionary variation in the known antigens of Mtb suggests that T cell recognition of those antigens is not detrimental to the pathogen or beneficial to the host. Through a comprehensive analysis of genomes from 216 phylogenetically diverse Mtb, my advisor and his colleagues discovered a distinct subset of Mtb antigens that are sequence variable and exhibit evidence of evolutionary selection pressure. In a screen of DNA vaccines encoding these sequence variable antigens, I discovered one (encoding 4 sequence variable antigens) that alters immunopathology and inflammatory Th1 responses in mice subsequently challenged with Mtb, without reducing lung bacterial burdens. Additional studies in our laboratory have demonstrated distinct CD4 T cell effector responses to these same antigens in humans. From these and other results, we hypothesize that a functionally distinct T cell response to one or more of our vaccine antigens is responsible for altered immunopathology in vaccinated mice after challenge. The objective of this proposal is to characterize the cellular responses in vaccinated mice after challenge and identify the mechanism that accounts for altered immunopathology. I will characterize the cellular response using spectral flow cytometry and immunofluorescence microscopy. I will then characterize the vaccine-specific T cell response using peptide:MHC tetramers and single cell RNA sequencing to identify potential mechanisms mediating the altered immunopathology response. Finally, I will identify the underlying mechanism(s) by performing adoptive transfers of sorted T cells to identify the phenotype of the T cells that alter immunopathology during infection. This work will identify differential T cell responses to distinct Mtb antigens and demonstrate a role of immunoregulation in mediating a vaccine response to Mtb infection. The findings will provide an understanding of T cell responses to Mtb antigens that can modulate immunopathology. This will provide a framework of vaccine-induced immunoregulatory responses to inform development of POD vaccines for Mtb.
摘要 结核病(TB)是一个主要的全球健康威胁,也是唯一获得许可的结核病疫苗 (卡介苗)是不够的:尽管广泛使用卡介苗,2020年全球仍有990万新结核病病例。 因此,迫切需要改进的结核分枝杆菌疫苗。T细胞反应仍然是结核病的主要目标 疫苗,如CD4T细胞,对于控制人类和动物模型中的结核分枝杆菌是必要的。T细胞疫苗已经被 到目前为止,在预防感染方面还不成功,但最近的M72-AS01E临床试验显示,~50% 作为预防疾病(POD)疫苗的效力。由于结核病是由患有活动性疾病的人传播的, 以炎症和免疫病理学为特征,是一种减少或预防活动性疾病的疫苗 免疫病理学可以对全球结核病问题产生很大影响。然而,最理想的抗原 结核疫苗的靶标(S)没有确定,结核分枝杆菌的已知抗原缺乏进化变异 提示T细胞对这些抗原的识别不会对病原体有害,对宿主也没有好处。 通过对216个系统发育不同的结核分枝杆菌的基因组进行综合分析,我的顾问和他的 同事们发现了结核分枝杆菌抗原的一个独特的子集,它们是序列可变的,并显示出 进化性选择的压力。在编码这些序列可变抗原的DNA疫苗的筛选中,即 发现一种(编码4个序列可变抗原)可改变免疫病理学和炎症性Th1 随后用结核分枝杆菌挑战小鼠的反应,没有减少肺部细菌负荷。其他研究 我们实验室的研究人员已经证明,人类对这些相同的抗原有明显的CD4T细胞效应器反应。 根据这些和其他结果,我们假设功能上不同的T细胞对我们的一个或多个 疫苗抗原是免疫小鼠免疫后免疫病理改变的原因。目标是 这项建议的目的是表征接种疫苗的小鼠在攻击后的细胞反应,并确定 解释免疫病理改变的机制。我将用光谱来描述细胞的反应 流式细胞术和免疫荧光显微镜。然后我将描述疫苗特异性T细胞反应的特征 利用多肽:MHC四聚体和单细胞RNA测序来确定可能的机制 免疫病理反应改变。最后,我将通过执行领养来确定潜在的机制(S 分选的T细胞的转移,以确定在感染期间改变免疫病理的T细胞的表型。 这项工作将识别不同的结核分枝杆菌抗原的不同T细胞反应,并展示 介导疫苗对结核分枝杆菌感染反应的免疫调节。这些发现将为我们提供一个理解 T细胞对结核分枝杆菌抗原的反应可以调节免疫病理。这将提供一个框架, 疫苗诱导的免疫调节反应,为结核分枝杆菌POD疫苗的开发提供信息。

项目成果

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Zachary Howard其他文献

Zachary Howard的其他文献

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{{ truncateString('Zachary Howard', 18)}}的其他基金

Mechanistic investigation of differential T cell responses to distinct Mycobacterium tuberculosis antigens
T 细胞对不同结核分枝杆菌抗原的差异反应的机制研究
  • 批准号:
    10536054
  • 财政年份:
    2022
  • 资助金额:
    $ 4.39万
  • 项目类别:

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