Protective Host Immunity Against Pulmonary Cryptococcosis

宿主对肺隐球菌病的保护性免疫

• 批准号: 9214307
• 负责人: Floyd L. Wormley
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214307
• 关键词: Acquired Immunodeficiency Syndrome; Antifungal Agents; Cells; Cessation of life; Clinical; Cryptococcal Meningitis; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Engineering; Epigenetic Process; Funding; HIV Seropositivity; Immune; Immune response; Immunity; Immunization; Immunize; Immunocompromised Host; Immunologics; Immunotherapy; Individual; Industrial fungicide; Infection; Inflammatory Response; Interferon-alpha; Intervention; Laboratories; Lead; Life; Liposomes; Lung; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Mycoses; Natural Immunity; Patients; Pharmacologic Substance; Role; STAT1 gene; STAT1 protein; Signal Transduction; T-Lymphocyte; Testing; Time; Training; Vaccines; antimicrobial; base; combat; design; expectation; histone modification; macrophage; mortality; novel; pathogen; prevent; programs; public health relevance

DESCRIPTION: Cryptococcus neoformans infections are a significant cause of morbidity and mortality among AIDS patients. Global estimates suggest that one million cases of cryptococcal meningitis occur each year resulting in over 625,000 deaths. Because host immune responses are so vital to the control of cryptococcosis, the overall objective of our laboratory is to determine the mechanism(s) necessary to elicit protective immunity against C. neoformans infections. To this end, the studies conducted during the previous funding period employed a C. neoformans strain engineered to express interferon (IFN)-γ, designated H99γ, to define protective immune responses against C. neoformans in mice. Importantly, we established for the first time that protective immunity against pulmonary cryptococcosis can be generated in T cell deficient hosts, thus providing "proof of concept" that vaccines targeting C. neoformans can elicit protection against cryptococcosis in immunocompromised patients. Additionally, preliminary results included herein show that signal transducer and activator of transcription 1 (STAT)-mediated classical macrophage (MΦ) activation is essential for the development of protective immunity against pulmonary cryptococcosis. Moreover, MΦs isolated from protectively immunized mice several weeks post-immunization have enhanced pro-inflammatory responses against C. neoformans that are associated with changes in their epigenetic programming. These exciting results support a novel paradigm for "trained" innate immunity against fungal pathogens. Altogether, our studies lead us to hypothesize that STAT1 signaling in MΦs is essential for classical MΦ activation and the induction of vaccine-mediated immunity against pulmonary C. neoformans infection. We plan to test our hypothesis and accomplish our overall objective by pursuing the following Specific Aims: (1) define the role of STAT1 signaling in the initiation of classical MΦ activation and antimicrobial activity against C. neoformans, (2 determine the mechanism(s) that facilitates STAT1-mediated classical MΦ activation and protection following immunization with C. neoformans strain H99γ, and (3) identify the epigenetic changes within MΦs of protectively immunized mice that are associated with protective immunity against C. neoformans.

描述：新型隐球菌感染是艾滋病患者发病和死亡的一个重要原因。全球估计每年发生 100 万例隐球菌性脑膜炎，导致超过 625,000 人死亡。由于宿主免疫反应对于控制隐球菌病至关重要，因此我们实验室的总体目标是确定引发针对新型隐球菌感染的保护性免疫所需的机制。为此，在上一个资助期间进行的研究采用了一种新型隐球菌菌株，该菌株经过改造可表达干扰素（IFN）-γ（命名为H99γ），以确定小鼠中针对新型隐球菌的保护性免疫反应。重要的是，我们首次证实在T细胞缺陷的宿主中可以产生针对肺隐球菌病的保护性免疫力，从而提供了“概念证明”，即针对新型隐球菌的疫苗可以在免疫功能低下的患者中引起针对隐球菌病的保护。此外，本文包含的初步结果表明，信号转导器和转录激活剂 1 (STAT) 介导的经典巨噬细胞 (MΦ) 激活对于肺隐球菌病保护性免疫的发展至关重要。此外，在免疫后几周从保护性免疫小鼠中分离出的 MΦ 增强了针对新型隐球菌的促炎症反应，这与其表观遗传编程的变化有关。这些令人兴奋的结果支持了针对真菌病原体“训练”的先天免疫的新范例。总而言之，我们的研究使我们假设 MΦ 中的 STAT1 信号传导对于经典 MΦ 激活和诱导针对肺部新型隐球菌感染的疫苗介导的免疫至关重要。我们计划通过追求以下具体目标来检验我们的假设并实现我们的总体目标：(1) 定义 STAT1 信号传导在经典 MΦ 激活和针对新型隐球菌的抗菌活性启动中的作用，(2 确定在用新型隐球菌菌株 H99γ 免疫后促进 STAT1 介导的经典 MΦ 激活和保护的机制，以及 (3) 识别其中的表观遗传变化 保护性免疫小鼠的 MΦ 与针对新型隐球菌的保护性免疫相关。