Protective Host Immunity Against Pulmonary Cryptococcosis

描述：新型隐球菌感染是艾滋病患者发病和死亡的重要原因。全球估计数字表明，每年发生100万例隐球菌脑膜炎病例，导致62.5万多人死亡。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引起对新生隐球菌感染的保护性免疫的必要机制。为此，在之前的资助期内进行的研究使用了一种新型C. formans菌株来表达干扰素(IFN)-？，指定H99?？，以确定小鼠对新生梭状菌的保护性免疫反应。重要的是，我们首次证实了对肺隐球菌病的保护性免疫可以在T细胞缺陷宿主中产生，从而提供了“概念证明”，即针对新生隐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。此外，本文包括的初步结果表明，信号换能器和转录激活因子1 （STAT）介导的经典巨噬细胞（M?）激活对于肺隐球菌病保护性免疫的发展至关重要。此外,M ?免疫几周后，从保护性免疫小鼠中分离出的C. 5增强了对新生梭状菌的促炎反应，这与它们的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“训练”先天免疫对抗真菌病原体的新范式。总之，我们的研究使我们假设M？s对于经典的M？激活和诱导疫苗介导的抗肺部新生梭状菌感染的免疫。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)定义STAT1信号在经典M？对新生C. formans的激活和抗菌活性(2)确定了促进stat1介导的经典M？新形式C. H99株免疫后的激活和保护作用(3)确定M？保护性免疫小鼠与对新生梭状芽孢杆菌的保护性免疫有关。

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.