Molecular Basis of Human Toxoplasmosis

 描述(申请人提供)：弓形虫是一种常见的人类寄生虫感染，通常会引起不复杂但持续的感染。慢性感染的重新激活可能会导致免疫功能低下的患者患上严重疾病，包括艾滋病毒/艾滋病患者。随着HAART疗法的出现，弓形虫病的发生率已经下降。然而，世界上仍有许多地区和易感人群，被晚期HAART治疗没有得到广泛或有效的实施。因此，由于慢性感染的高流行率和现有抗生素的局限性，弓形虫病对免疫功能低下的患者构成了持续的风险，而现有抗生素无法根除慢性感染。我们的研究旨在确定弓形虫致病的分子基础，重点放在毒力更强的寄生虫谱系上，这些寄生虫可能会对免疫受损的患者构成更大的风险。我们以前曾使用北美克隆谱系的遗传分析来鉴定弓形虫的毒力基因。然而，弓形虫的菌株更加多样化，在世界其他地区进行了更多的遗传交流。例如，在小鼠模型中，大多数南美毒株都是剧毒的，这些毒株经常在艾滋病毒阳性患者中发现，这些患者会导致严重的中枢神经系统疾病。这种增强致病性的基础目前尚不清楚，但重要的是，它不能用已知的毒力决定因素来解释。在初步研究中，我们在南美毒力强的菌株和北美典型的毒力较低的谱系之间开发了几个新的遗传杂交。拟议的研究将使用遗传图谱来识别弓形虫的毒力决定因素，并测试这些寄生虫效应器在调节人类细胞生存中的作用。在初步研究中，我们已经证明，干扰素-激活的人类细胞以一种菌株特异性的方式限制弓形虫的生长。拟议的研究将确定人类细胞中这种耐药途径的细胞和分子基础。遗传方法将被用来鉴定寄生虫毒力的分子决定因素。我们研究的总体目标是 明确弓形虫克服宿主抗性的分子机制，从而提高其存活率并导致更严重的疾病。成功识别寄生虫毒力因素可能导致改进检测和/或改进旨在对抗感染的干预措施。

 DESCRIPTION (provided by applicant): Toxoplasma gondii is a common parasitic infection of humans where it normally causes uncomplicated yet persistent infections. Reactivation of chronic infection can lead to severe disease in immunocompromised patients, including those with HIV-AIDS. With the advent of HAART therapy, the frequency of toxoplasmosis has decreased. However, there are still many areas of the world, and susceptible patient populations, were advanced HAART therapy is not widely or effectively implemented. Hence, toxoplasmosis presents a continued risk to immunocompromised patients due to the high prevalence of chronic infection and limitations of existing antibiotics, which do not eradicate chronic infections. Our studies are designed to define the molecular basis of pathogenesis in T. gondii, focusing on more virulent parasite lineages that may pose greater risk in immunocompromised patients. We have previously used genetic analyses of the clonal lineages of North America to identify virulence genes in T. gondii. However, T. gondii strains are much more diverse and undergo greater genetic exchange in other regions of the world. For example, the majority of South American strains are acutely virulent in the mouse model and such strains are frequently found in HIV positive patients where they cause severe CNS disease. The basis for this enhanced pathogenicity is presently unknown, but importantly, it cannot be explained by known virulence determinants. In preliminary studies, we have developed several new genetic crosses between highly virulent South American strains and less virulent lineages typical of North America. The proposed studies will use genetic mapping to identify virulence determinants of T. gondii and test the role of these parasite effectors in mediating survival in human cells. In preliminary studies, we have shown that IFN--activated human cells restrict the growth of T. gondii in a strain-specific manner. The proposed studies will define the cellular and molecular basis of this resistance pathway in human cells. Genetic approaches will be used to identify the molecular determinants of parasite virulence. The overall goal of our studies is to define the molecular mechanisms by which T. gondii overcomes host resistance, thus enhancing its survival and leading to more severe disease. Successful identification of parasite virulence factors may lead to improved detection and/or improved interventions designed to combat infection.