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：艾滋病患者中的加密型新甲壳虫感染是发病率和死亡率的重要原因。全球估计表明，每年有100万例隐球菌脑膜炎病例导致62.5万人死亡。由于宿主免疫调查对于控制隐孢子球的控制至关重要，因此我们实验室的总体目标是确定引起针对Neoformans C. Neoformans感染的保护免疫学所必需的机制。为此，在上一个资金期间进行的研究采用了为表达干扰素（IFN）-γ（指定为H99γ）设计的C. neoformans菌株，以定义小鼠中针对Neoformans的受保护的免疫复杂。重要的是，我们首次确定可以在缺乏T细胞的宿主中生成保护免疫组织性侵害肺隐球菌的免疫组织性，因此提供了“概念证明”，以使靶向Neoformans的疫苗可以在不受影响的患者的患者中引起靶向Neoformans的疫苗。此外，本文包括的初步结果表明，转录1（STAT）介导的经典巨噬细胞（Mφ）激活的信号换能器和激活因素对于开发受保护的免疫组织化学显微关节crompococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococococosis至关重要。此外，免疫后数周从受保护的免疫小鼠中分离出来的MφS增强了与新生梭菌的促炎反应，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的“训练”先天免疫学的新型范式。总的来说，我们的研究使我们假设MφS中的STAT1信号对于经典的Mφ激活和诱导疫苗介导的免疫学对肺C. Neoformans感染至关重要。我们计划通过追求以下特定目的来检验我们的假设并实现我们的总体目标：（1）定义STAT1信号在启动经典Mφ激活和针对Neoformans的抗菌活性中的作用（2确定促进STAT1介导的经典Mφ激活和保护性的机制，并识别C. neoformants c. neoforments（3）在受保护的免疫对抗梭状芽胞杆菌的免疫相关的受保护的免疫小鼠的Mφ中。