Strain-specific host-pathogen interactions in toxoplasmosis

弓形虫病中菌株特异性宿主-病原体相互作用

• 批准号: 8099425
• 负责人: John C Boothroyd
• 金额: $ 38.07万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099425
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Alleles; Animal Model; Animals; Attention; Back; Binding; Biological; Blindness; Candidate Disease Gene; Cells; Chromosome Mapping; Clinical; Computer software; Cosmids; Data; Disease; Disease Outcome; Disease Progression; Engineering; Environmental Risk Factor; Fetus; Fibroblasts; Gene Expression; Genes; Genome; Goals; Haplotypes; Human; Immune response; Immune system; Immunocompromised Host; Immunofluorescence Immunologic; Immunoprecipitation; Immunosuppressive Agents; In Vitro; Infection; Integration Host Factors; Knock-in Mouse; Knock-out; Life; Livestock; Maps; Mass Spectrum Analysis; Measures; Methods; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Mus; Outcome; Parasites; Patients; Phenotype; Phosphotransferases; Plasmids; Play; Property; Proteins; Recombinants; Side; Steroids; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vacuole; Virulence; Work; base; genome-wide; genome-wide analysis; in vivo; macrophage; mouse genome; mutant; obligate intracellular parasite; pathogen; penis foreskin; programs; promoter; response

DESCRIPTION (provided by applicant): Toxoplasma gondii is a serious pathogen of humans and livestock in the U.S.A. and world-wide. In addition to its well-known disease-causing abilities in the developing fetus, in the past two decades this protozoan parasite has increased its notoriety through the fatal disease it can cause in AIDS patients. Many studies have shown that the disease outcome in animals and probably people is dependent on which strain of the parasite is responsible for the infection. Knowing the basis for these differences is of great clinical importance in allowing the treatment to be matched to the specifics of the infection. For example, some strains may produce the most serious consequences through an excessive immune response rather than through direct tissue destruction by the parasite itself. Conversely, other strains may be so invasive that the immune response can't keep up and so the patient is overwhelmed by the parasite. Treating these two scenarios requires completely different strategies: in one, steroids or other immunosuppressive treatments might be the best choice while in the other, the immune system may need to be helped, not impaired, and rapid treatment with anti-parasite agents is needed. The goal of our work is to understand the molecular basis for strain-specific differences in the host-pathogen interaction. Our approach has been to use a combination of in vitro and in vivo studies to compare different strains and thereby acquire a detailed understanding of the phenomenology behind the different phenotypes. We use genome-wide analysis of how different strains interact with the infected host cell as well as detailed in vivo analysis that follows the exact progression of disease using methods that allow the infection to be monitored in live animals in a non-invasive way. Once these phenotypes are determined, we use crosses between the different strains of Toxoplasma to map the genes involved. Finally, we employ a combination of molecular genetic and cell biological approaches to verify the involvement of the candidate genes and determine the mechanism of their action with special attention to how the different alleles play out as differences in disease-causing properties.

描述（由申请人提供）：弓形虫Gondii是美国和世界范围内人类和牲畜的严重病原体。除了其在发育中的胎儿中著名的致病能力外，在过去的二十年中，这种原生动物寄生虫通过可能在艾滋病患者中引起的致命疾病提高了其声名狼藉。许多研究表明，动物以及人们的疾病结果取决于寄生虫的哪种菌株导致感染。了解这些差异的基础在允许治疗与感染的细节相匹配方面非常重要。例如，某些菌株可能会通过过度的免疫反应而不是通过寄生虫本身的直接组织破坏产生最严重的后果。相反，其他菌株可能是如此侵入性，以至于免疫反应无法保持不变，因此患者被寄生虫淹没了。治疗这两种情况需要完全不同的策略：一方面，类固醇或其他免疫抑制治疗可能是最佳选择，而另一方面，可能需要帮助，而不是受损的免疫系统，并且需要对抗寄生虫剂进行快速治疗。我们工作的目的是了解宿主病原体相互作用菌株特异性差异的分子基础。我们的方法是使用体外和体内研究的组合来比较不同的菌株，从而详细了解不同表型背后的现象学。我们使用全基因组分析，分析不同菌株如何与受感染的宿主细胞相互作用，并使用详细的体内分析，该分析遵循疾病的确切进展，使用允许以非侵入性方式在活动物中监测感染的方法。一旦确定了这些表型，我们就会在不同的弓形虫菌株之间使用杂交来绘制所涉及的基因。最后，我们采用了分子遗传学和细胞生物学方法的组合来验证候选基因的参与，并特别注意其作用的机制，特别注意不同等位基因如何表现为引起疾病的特性的差异。