Strain-specific Host-Pathogen Interactions in Toxoplasmosis

弓形体病中菌株特异性宿主-病原体相互作用

• 批准号: 8611989
• 负责人: John C Boothroyd
• 金额: $ 3.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611989
• 关键词: Address; Alleles; Amino Acid Sequence; Animals; Biological; Cell Line; Cells; Clinical Research; Complement; Cytoplasmic Granules; Data; Disease; Disease Outcome; Fibroblasts; Funding; Genes; Genetic; Goals; Human; Image; Immune response; Immune system; In Vitro; Infection; Interferon Type I; Interferons; Light; Malaria; Measures; Mediating; Membrane; Metabolism; Mitochondria; Molecular; Molecular Genetics; Natural Immunity; Nature; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Patients; Peptide Sequence Determination; Phenotype; Play; Production; Proteins; Reactive Oxygen Species; Recruitment Activity; Role; Side; Signal Transduction; Structure; Symptoms; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vacuole; Virulence; Work; base; in vivo; innate immune function; insight; macrophage; parasite genome; pathogen; research study; response; rhoptry; stem; trait

DESCRIPTION (provided by applicant): The disease that Toxoplasma causes in humans ranges from essentially asymptomatic to debilitating or even fatal. There are likely many reasons for this difference but unambiguous evidence from animal studies and recent data from clinical studies in humans indicate that strain differences in the parasite likely play a major rol. Genetic studies of the parasite have led to the identification of a small number of genes that differ between strains and that interface with the innate immune system in dramatically different ways. The on-going goals of this work are to identify these proteins and determine the molecular basis for their strain-specific effects. In the prior funding period, it was discovered that the recruitment of host mitochondria to the parasitophorous vacuole is a strain-specific phenomenon and the gene responsible for this difference, "mitochondrial-association factor 1" or MAF1, was identified. The first aim of the current proposal is to determine how MAF1 recruits mitochondria, the precise nature of the strain-specific differences in its action and the downstream consequences in terms of interactions with the host. Mitochondria are being increasingly recognized as key to innate immune functions and so these differences are likely to play out in important ways in pathogenesis. Macrophages are key players in some of the earliest immune responses and progress in the first funding period revealed a role for several polymorphic Toxoplasma genes in mediating the response of these cells. The second aim of the current proposal is to identify the genes responsible for two of these strain-specific differences and determine the molecular basis for the downstream effects that are observed. Both aims will be accomplished through a combination of molecular genetics, imaging and in vivo studies.

描述（由申请人提供）：弓形虫在人类中引起的疾病范围从基本无症状到使人衰弱甚至致命。造成这种差异的原因可能有很多，但动物研究的明确证据和人类临床研究的最新数据表明，寄生虫的菌株差异可能发挥着重要作用。对寄生虫的遗传学研究已经鉴定出少数基因，这些基因在菌株之间存在差异，并且以截然不同的方式与先天免疫系统相互作用。这项工作的持续目标是识别这些蛋白质并确定其菌株特异性作用的分子基础。 在之前的资助期间，人们发现宿主线粒体向寄生液泡的募集是一种菌株特异性现象，并且确定了造成这种差异的基因“线粒体关联因子1”或MAF1。当前提案的第一个目标是确定 MAF1 如何招募线粒体、其作用中菌株特异性差异的确切性质以及与宿主相互作用的下游后果。人们越来越认识到线粒体是先天免疫功能的关键，因此这些差异可能在发病机制中以重要方式发挥作用。 巨噬细胞是一些最早的免疫反应的关键参与者，第一个资助期的进展揭示了几种多态性弓形虫基因在介导这些细胞反应中的作用。当前提案的第二个目标是确定导致其中两个菌株特异性差异的基因，并确定观察到的下游效应的分子基础。这两个目标将通过分子遗传学、成像和体内研究的结合来实现。