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

基本信息

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
项目类别：
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

项目摘要

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）：弓形虫是美国和全世界人类和牲畜的严重病原体。除了众所周知的在发育中的胎儿中致病的能力之外，在过去的二十年中，这种原生动物寄生虫还因为它可以在艾滋病患者中引起致命的疾病而变得更加恶名昭彰。许多研究表明，动物（甚至可能是人类）的疾病结果取决于引起感染的寄生虫菌株。了解这些差异的基础对于使治疗与感染的具体情况相匹配具有重要的临床意义。例如，某些菌株可能通过过度的免疫反应而不是通过寄生虫本身直接破坏组织来产生最严重的后果。相反，其他菌株可能具有很强的侵袭性，以至于免疫反应无法跟上，因此患者会被寄生虫淹没。治疗这两种情况需要完全不同的策略：在一种情况下，类固醇或其他免疫抑制治疗可能是最佳选择，而在另一种情况下，免疫系统可能需要帮助而不是受损，并且需要使用抗寄生虫药物进行快速治疗。我们工作的目标是了解宿主与病原体相互作用中菌株特异性差异的分子基础。我们的方法是结合体外和体内研究来比较不同的菌株，从而详细了解不同表型背后的现象学。我们对不同菌株如何与受感染的宿主细胞相互作用进行全基因组分析，并使用能够以非侵入性方式监测活体动物感染的方法，对疾病的确切进展进行详细的体内分析。一旦确定了这些表型，我们就利用不同弓形虫菌株之间的杂交来绘制所涉及的基因图谱。最后，我们采用分子遗传学和细胞生物学相结合的方法来验证候选基因的参与并确定其作用机制，特别关注不同等位基因如何发挥致病特性的差异。