Induction of Th1-type Protective Immunity to Listeria

对李斯特菌的 Th1 型保护性免疫的诱导

• 批准号: 7213367
• 负责人: Sing Sing Way
• 金额: $ 1.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213367
• 关键词: Induction; Th1; type; Protective; Immunity

DESCRIPTION (provided by applicant): On a global scale, infectious agents as a group are the leading cause of mortality in infants, children, and adults. With its focus on disease prevention, vaccination is one of the most efficacious and cost effective means for infectious disease control. However in order to design safe and effective vaccines, a better understanding of how adaptive immune responses are generated and the specific immunological conditions during antigen exposure that will confer long-lived protection is needed. In addition to their role in triggering innate immune responses, the Toll-like receptor (TLR) family of molecules is believed to play essential roles in controlling the adaptive immune response by facilitating the generation of antigen-specific Thl-(IFN-yproducing) CD4 T cells. In the absence of TLRs or the downstream signaling molecule, MyD88, most infections or immunizations trigger an exclusive Th2-(no IFN-y produced, and IL-4 and IL-13 produced instead) immune response. Listeria monocytogenes (Lm) is a major pathogen in the neonate and in other immune-compromised hosts; and in the absence of TLR/MyD88, Lm infection retains the ability to generate IFN-y producing CD4 and CDS T cells. An analysis of the mechanistic basis for TLR/MyD88-independent generation of Thl immunity will be important for designing vaccines that aim to trigger this type of immune response, and will require me to become proficient with cellular immunology techniques that I yet do not have. We hypothesize (1) that entry into the cell cytoplasm and induction of type I-IFNs distinguish Lm from other infection and immunization models and allow Lm to induce Thl-immunity in the absence of TLR/MyD88 and (2) that regulatory T cells (normally inhibited by TLR-dependent pathways) can also be inhibited during Lm infection despite the lack of TLR-mediated cell activation. To test the role of Lm cytoplasmic entry and induction of type I-IFNs, we will examine the immune response following infection with Lm mutants that cannot gain access to the cell cytoplasm, and in mice with targeted disruption of type IIFN receptor. To test the role of regulatory T cells, we will isolate these cells during Lm infection and examine their function both in vitro and following adoptive transfer in vivo. The studies proposed will begin to characterize the mechanistic details of a TLR-independent pathway by which Thl-adaptive immune responses can be generated, and serve as the preliminary experiments for my transition into an independent investigator in the fields of immunology and infectious disease.

描述（由申请人提供）：在全球范围内，感染性病原体作为一个群体是婴儿、儿童和成人死亡的主要原因。疫苗接种以疾病预防为重点，是控制传染病最有效和最具成本效益的手段之一。然而，为了设计安全有效的疫苗，需要更好地了解适应性免疫反应是如何产生的，以及抗原暴露期间赋予长期保护的特定免疫条件。除了在触发先天免疫应答中发挥作用外，toll样受体（TLR）分子家族被认为通过促进抗原特异性Thl-（ifn生成）CD4 T细胞的产生，在控制适应性免疫应答中发挥重要作用。在缺乏TLRs或下游信号分子MyD88的情况下，大多数感染或免疫触发排他的Th2-（不产生IFN-y，而是产生IL-4和IL-13）免疫反应。单核细胞增生李斯特菌（Lm）是新生儿和其他免疫功能低下宿主的主要病原体；在TLR/MyD88缺失的情况下，Lm感染保留了产生IFN-y的CD4和CDS T细胞的能力。分析不依赖TLR/ myd88产生Thl免疫的机制基础对于设计旨在触发这种免疫反应的疫苗非常重要，并且需要我精通我尚未掌握的细胞免疫学技术。我们假设：(1)进入细胞质和诱导i型ifn将Lm与其他感染和免疫模型区分出来，并允许Lm在缺乏TLR/MyD88的情况下诱导thl免疫；(2)尽管缺乏TLR介导的细胞激活，但在Lm感染期间，调节性T细胞（通常被TLR依赖途径抑制）也可以被抑制。为了测试Lm细胞质进入和诱导i型ifn的作用，我们将检测无法进入细胞质的Lm突变体感染后的免疫反应，以及靶向破坏IIFN受体的小鼠。为了测试调节性T细胞的作用，我们将在Lm感染期间分离这些细胞，并在体外和体内过继转移后检查它们的功能。提出的研究将开始描述tlr独立途径的机制细节，通过该途径可以产生thl适应性免疫反应，并作为我过渡到免疫学和传染病领域的独立研究者的初步实验。