Protective Host Immunity Against Pulmonary Cryptococcosis

描述：新生隐球菌感染是艾滋病患者发病和死亡的重要原因。全球估计表明，每年发生100万例隐球菌性脑膜炎，导致625,000多人死亡。由于宿主免疫反应对控制隐球菌病至关重要，我们实验室的总体目标是确定诱导保护性免疫抵抗新生隐球菌病感染所需的机制(S)。为此，在之前的资助期间进行的研究使用了一种经工程改造为表达干扰素(干扰素)的新生葡萄球菌菌株，命名为H99？，以确定小鼠对新生葡萄球菌的保护性免疫反应。重要的是，我们首次证实T细胞缺乏的宿主可以产生对肺隐球菌病的保护性免疫，从而提供了针对新生葡萄球菌的疫苗可以在免疫功能低下的患者中引起对隐球菌病的保护的“概念证据”。此外，本文的初步结果表明，信号转导和转录激活因子1(STAT)介导的经典巨噬细胞(M？)激活对于发展对肺隐球菌病的保护性免疫是必不可少的。此外，免疫后几周从保护性免疫小鼠中分离出的M？S增强了对新生葡萄球菌的促炎反应，这与其表观遗传程序的变化有关。这些令人兴奋的结果支持了一种针对真菌病原体的“训练有素”的先天免疫的新范例。综上所述，我们的研究使我们假设M？S的STAT1信号是经典M？肺部新生葡萄球菌感染疫苗介导免疫的激活和诱导。我们计划通过追求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STAT1信号在经典M？对新生葡萄球菌的激活和抗菌活性，(2确定了促进STAT1介导的经典M？新生弧菌H99株免疫后的激活和保护；(3)鉴定保护性免疫小鼠M？S体内与保护性免疫相关的表观遗传学变化。

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)-?, designated H99??, 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 (M?) activation is essential for the development of protective immunity against pulmonary cryptococcosis. Moreover, M?s 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 M?s is essential for classical M? 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 M? activation and antimicrobial activity against C. neoformans, (2 determine the mechanism(s) that facilitates STAT1-mediated classical M? activation and protection following immunization with C. neoformans strain H99?, and (3) identify the epigenetic changes within M?s of protectively immunized mice that are associated with protective immunity against C. neoformans.