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率和死亡率的重要原因。全球估计表明，每年发生100万例隐球菌脑膜炎，导致625，000多人死亡。由于宿主免疫反应对隐球菌病的控制至关重要，我们实验室的总体目标是确定引起针对隐球菌的保护性免疫所必需的机制。新型感染。为此，在上一个资助期内进行的研究采用了C。新变形杆菌菌株工程化以表达干扰素（IFN）-γ，命名为H99γ，以定义针对C.小鼠体内的新形式。重要的是，我们第一次确定了在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，从而提供了靶向C.新型隐球菌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，本文包括的初步结果表明，信号转导子和转录激活子1（STAT）介导的经典巨噬细胞（MΦ）激活对肺隐球菌病的保护性免疫的发展是必不可少的。此外，从免疫后数周的保护性免疫小鼠中分离的MΦ具有增强的针对C.与其表观遗传程序的变化有关的新生儿。这些令人兴奋的结果支持了一个新的模式，“训练”先天免疫对真菌病原体。总之，我们的研究使我们假设MΦs中的STAT 1信号传导对于经典MΦ活化和诱导疫苗介导的抗肺C的免疫是必不可少的。新生儿感染。我们计划通过以下具体目标来验证我们的假设并实现我们的总体目标：（1）确定STAT 1信号在经典MΦ激活和抗C. 新生儿，（2）确定促进STAT 1介导的经典MΦ活化和免疫后C.新生隐球菌菌株H99γ，和（3）鉴定保护性免疫小鼠MΦs内与针对C.新人类