Toxoplasma strain-specific modulation of mouse immune cells

描述（由申请方提供）：弓形虫是一种专性细胞内寄生虫，可在免疫功能低下的患者和发育中的胎儿中引起严重疾病。大多数从欧洲和北美的人类患者和牲畜中分离的弓形虫属于三种遗传上不同的菌株之一，即I型、II型和III型菌株。在小鼠中，这三种不同的菌株在毒力和其他表型方面存在巨大差异，并且有充分的证据表明在人类中也是如此。了解这些不同的弓形虫菌株如何在引起疾病方面不同具有重要的临床意义;一些菌株可能通过过度刺激免疫反应导致细胞因子的毒性水平而引起疾病，而其他菌株可能主要通过大量寄生虫引起的组织损伤引起疾病。如果知道不同的弓形虫株如何引起疾病以及患者感染的是哪种株，则可以根据感染的具体情况进行治疗;在某些情况下，抑制免疫反应可能是最佳选择，而在其他情况下，可能需要用抗寄生虫剂进行积极治疗。我们的假设是，除了宿主和环境因素，弓形虫株的基因型通过调节宿主细胞信号通路的菌株之间的差异在确定疾病结果中起着重要作用。因此，该基金的目标是鉴定和表征弓形虫基因产物，这些基因产物参与宿主细胞信号通路的菌株特异性调节。我们将首先确定弓形虫强毒株和无毒毒株在体内调节小鼠先天免疫细胞信号通路方面的差异。然后，我们将使用现有的F1后代从这些菌株之间的杂交，以映射弓形虫基因组区域。随后，我们将利用分子遗传学方法鉴定弓形虫相关基因。最后，我们将描述这些基因的作用机制。为了寄生虫自己的目的而选择宿主信号传导途径的能力可能在也生活在膜限制的空泡内的其他顶复门中发现，例如，疟原虫物种在肝细胞内生长。因此，预计对弓形虫用于调节宿主细胞信号传导的机制的透彻理解将导致针对这种和其他顶复门寄生虫的更好的疗法。

DESCRIPTION (provided by applicant): Toxoplasma is an obligate intracellular parasite that can cause serious disease in immunocompromised patients and in the developing fetus. The majority of Toxoplasma isolates from human patients and livestock in Europe and North-America belong to one of three genetically distinct strains, the type I, type II and type III strains. In mice, these three distinct strains differ enormously in virulence and other phenotypes and there is good evidence that in humans this is also the case. Understanding how these distinct Toxoplasma strains differ in causing disease has important clinical implications; some strains may cause disease through over-stimulation of the immune response leading to toxic levels of cytokines while other strains may cause disease mainly through tissue damage caused by the large numbers of parasites present. If it was known how distinct Toxoplasma strains cause disease and with what strain a patient was infected the treatment could be matched to the specifics of the infection; in some cases inhibition of the immune response might be the best choice while in other cases aggressive treatment with anti-parasitic agents might be needed. Our hypothesis is that, besides host and environmental factors, the genotype of the Toxoplasma strain plays a major role in determining disease outcome through differences between strains in modulating host cell signaling pathways. The goal of this grant is therefore the identification and characterization of Toxoplasma gene products involved in strain-specific modulation of host cell signaling pathways. We will first determine differences between virulent and avirulent strains of Toxoplasma in modulating signaling pathways in mouse innate immune cells in vivo. We will then use existing F1 progeny from crosses between these strains to map the Toxoplasma genomic regions involved. Subsequently, we will use molecular genetic approached to identify the Toxoplasma genes involved. Finally, we will characterize the mechanism of action of these genes. The ability to co-opt host signaling pathways for the parasite's own purposes is likely to be found in other Apicomplexa that are also living within a membrane-limited vacuole, for example, Plasmodium species as they grow within hepatocytes. It is therefore expected that a thorough understanding of the mechanisms Toxoplasma uses to modulate host cell signaling will lead to better therapies against this and other Apicomplexan parasites.