Autophagic Defense Against Intracellular Parasites

描述（由申请人提供）：顶复合体寄生虫，弓形虫和疟原虫是人类最流行和最重要的两种寄生虫病。这类寄生虫的成功在于它们能够形成寄生液泡（pv），从而避免与宿主细胞溶酶体融合和破坏。我们最近发现了一种新的途径，通过破坏PV膜和随后在暴露的病原体周围形成自噬液泡来免疫破坏这些寄生虫。利用一项新开发的巨噬细胞细胞内杀伤弓形虫寄生虫的离体实验，我们将首先确定ifn - γ受体信号和IGTP与CD40和tnf受体信号在介导寄生虫自噬消除中的单独和联合作用。我们还将确定病原体的毒力菌株是否已经发展并产生阻止巨噬细胞消除侵入性寄生虫的能力的因子。抗cd40治疗克服宿主防御反应的能力将被评估，这种防御反应是由寄生虫的毒力菌株或ifn - γ反应途径的遗传缺陷造成的。该研究将促进对宿主-寄生虫免疫关系的基本理解，并确定通过诱导自噬增强宿主对细胞内病原体防御的具体策略。公共卫生相关性：由顶复寄生虫、弓形虫病和疟疾引起的感染是人类最重要的两种寄生虫病。我们最近描述了一种通过病原体液泡破坏和自噬消除来免疫清除这种寄生虫的新机制。在这个NIH的探索性提议中，我们的研究将产生重要的信息，如何调节免疫反应，并可以被操纵来促进这种类型的抗寄生虫宿主防御。

DESCRIPTION (provided by applicant): Apicomplexan parasites, Toxoplasmaand Plasmodiumare two of the most prevalent and important parasitic diseases of mankind. The success of this class of parasite lies in their ability to form parasite vacuoles (PVs) that avert fusion with and destruction by host cell lysosomes. We have recently discovered a novel pathway for immune destruction of these parasites by disruption of the PV membrane and subsequent formation of an autophagic vacuole around the exposed pathogen. Using a newly developed ex vivo assay for intracellular killing of Toxoplasma gondii parasites by primed macrophages, we will first define the individual and combined roles of IFN-gamma receptor signaling and IGTP versus CD40 and TNF-receptor signaling in mediating autophagic elimination of the parasite. We will also determine whether virulent strains of the pathogen have developed and produce factor(s) that block the ability of the primed macrophages to eliminate invasive parasites. The ability of anti-CD40 treatment to surmount a blockade of this host defense response by virulent strains of the parasite or by genetic deficiencies in the IFN-gamma response pathway will be evaluated. The proposed research will advance basic understanding of the immune host-parasite relationship and pinpoint specific strategies for boosting host defenses to intracellular pathogens via induction of autophagy. PUBLIC HEALTH RELEVANCE: Infections caused by apicomplexan parasites, toxoplasmosis and malaria are two of the most important parasite diseases of mankind. We have recently described a new mechanism for immune clearance of this type of parasite by pathogen vacuole disruption and autophagic elimination. In this NIH exploratory proposal, our studies will yield important information how the immune response is regulated and can be manipulated to promote this type of anti-parasite host defense.