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: 7603005
• 负责人: Sing Sing Way
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603005
• 关键词: Adoptive Transfer; Adult; Antigens; Bacteria; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Cellular Immunology; Child; Communicable Diseases; Cytoplasm; Family; Generations; Immune; Immune response; Immunity; Immunization; Immunology; In Vitro; Infant; Infection; Infectious Agent; Infectious Disease Immunology; Interleukin-13; Interleukin-4; Life; Listeria; Listeria monocytogenes; Mammals; Mediating; Modeling; Mus; Pathway interactions; Play; Production; Research Personnel; Role; Shapes; Signaling Molecule; T-Lymphocyte; Techniques; Testing; Toll-like receptors; Vaccination; Vaccine Design; Vaccines; base; cost effective; design; disorder control; disorder prevention; in vivo; mortality; mutant; neonate; pathogen; research study; response; type I interferon receptor

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-y- producing) 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 I- IFN 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.

在全球范围内，感染性病原体作为一个群体是婴儿、儿童和 成年人。由于其重点是预防疾病，接种疫苗是最有效和最具成本效益的方法之一。 传染病控制手段。然而，为了设计安全有效的疫苗，更好的 了解获得性免疫反应是如何产生的，以及特定的免疫条件 在抗原暴露期间，需要提供长期保护。除了它们在触发 先天免疫反应，Toll样受体(TLR)家族分子被认为起着至关重要的作用 通过促进抗原特异性Th1-(干扰素-γ-)的产生来控制获得性免疫反应 产生)CD4T细胞。在没有TLR或下游信号分子的情况下，MyD88，大多数 感染或免疫会触发独有的Th2-(不产生干扰素-γ，产生IL-4和IL-13 相反)免疫反应。单核细胞增多性李斯特菌(Lm)是新生儿和其他疾病的主要病原体。 免疫受损的宿主；在缺乏TLR/MyD88的情况下，LM感染保持产生 产生干扰素-γ的CD4和CDS T细胞。TLR/MyD88非独立的力学基础分析 Thl免疫的产生对于设计旨在触发这种免疫类型的疫苗将是重要的 回应，并将要求我精通细胞免疫学技术，但我还不懂 有。我们假设(1)进入细胞质和诱导型I型IFN将LM区别于 其他感染和免疫模型，并允许LM在缺少THL的情况下诱导Thl免疫 TLR/MyD88和(2)调节性T细胞(通常被TLR依赖的通路抑制)也可以 在LM感染期间被抑制，尽管缺乏TLR介导的细胞激活。测试LM的作用 I型干扰素的细胞质进入和诱导，我们将检测感染后的免疫反应 对于不能进入细胞质的LM突变体，以及在I型靶向干扰的小鼠中- 干扰素受体。为了测试调节性T细胞的作用，我们将在LM感染和 在体外和体内过继移植后检测它们的功能。拟议的研究将开始 描述Th1获得性免疫中TLR非依赖途径的机制细节 可以生成响应，并作为我过渡到独立的 免疫学和传染病领域的研究员。