Autophagic Defense Against Intracellular Parasites

针对细胞内寄生虫的自噬防御

• 批准号: 7582295
• 负责人: George S. Yap
• 金额: $ 19.5万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582295
• 关键词: Address; Astrocytes; Autophagocytosis; Autophagosome; Biological Assay; Cell Line; Cell membrane; Cells; Cellular Immunity; Cessation of life; Cytosol; Defense Mechanisms; Disease; Effector Cell; Endocytosis; Ensure; Erythrocytes; Event; Genetic; Guanosine Triphosphate Phosphohydrolases; Host Defense; Host resistance; Host-Parasite Relations; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Interferon Gamma Receptor Complex; Interferon Type II; Interferons; Invaded; Laboratories; Ligation; Lysosomes; Malaria; Mediating; Mediator of activation protein; Medical Economics; Membrane; Methods; Microscopic; Parasite Control; Parasite resistance; Parasites; Parasitic Diseases; Pathway interactions; Physiological; Plasmodium; Play; Population; Publishing; Receptor Signaling; Reporting; Research; Resistance; Role; Series; Signal Transduction; Staging; System; TNF gene; TNFRSF5 gene; TNFSF5 gene; Testing; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Vaccines; Vacuole; Virulence; Virulent; blocking factor; cytokine; defense response; human AKAP13 protein; immune clearance; in vivo; killings; macrophage; member; novel; particle; pathogen; programs; research study; response; success

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.

描述（由申请人提供）：顶复门寄生虫，弓形虫和疟原虫是人类两种最流行和最重要的寄生虫病。这类寄生虫的成功在于它们能够形成寄生虫空泡（PV），从而避免与宿主细胞溶酶体融合和被宿主细胞溶酶体破坏。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空泡来免疫破坏这些寄生虫。使用新开发的体外试验通过致敏巨噬细胞细胞内杀死弓形虫寄生虫，我们将首先定义IFN-γ受体信号传导和IGTP与CD 40和TNF受体信号传导在介导自噬消除中的单独和组合作用寄生虫。我们还将确定病原体的强毒株是否已经发展并产生阻断引发的巨噬细胞消除侵入性寄生虫的能力的因子。将评价抗CD 40治疗克服寄生虫强毒株或IFN-γ应答途径中遗传缺陷对该宿主防御应答的阻断的能力。拟议的研究将推进对免疫宿主-寄生虫关系的基本理解，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。公共卫生关系：由顶复门寄生虫引起的感染，弓形虫病和疟疾是人类最重要的两种寄生虫病。我们最近描述了一种新的机制，免疫清除这种类型的寄生虫的病原体空泡破坏和自噬消除。在这个NIH探索性的提议中，我们的研究将产生重要的信息，即免疫反应是如何被调节的，以及如何被操纵来促进这种类型的抗寄生虫宿主防御。