Toxoplasma strain-specific modulation of mouse immune cells

描述(申请人提供)：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。来自欧洲和北美的人类患者和家畜的大多数弓形虫分离株属于三种不同的遗传菌株之一，即I型、II型和III型菌株。在小鼠身上，这三种不同的菌株在毒力和其他表型上存在巨大差异，有很好的证据表明，在人类中也是如此。了解这些不同的弓形虫菌株在致病方面的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毒性水平而致病，而其他菌株可能主要通过大量寄生虫引起的组织损伤而致病。如果知道不同的弓形虫菌株是如何致病的，以及患者是用什么菌株感染的，就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，可能需要使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外，弓形虫菌株的基因型通过调节宿主细胞信号通路的不同而在决定疾病结局方面发挥主要作用。因此，这项资助的目标是鉴定和鉴定弓形虫基因产物，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株在体内调节小鼠天然免疫细胞信号通路方面的差异。然后，我们将使用这些菌株之间杂交的现有F1后代来绘制所涉及的弓形虫基因组区域。随后，我们将使用分子遗传学的方法来鉴定涉及的弓形虫基因。最后，我们将描述这些基因的作用机制。为了寄生虫自身的目的而选择宿主信号通路的能力很可能在其他也生活在膜限制液泡中的顶复合体中找到，例如在肝细胞内生长的疟原虫物种。因此，对弓形虫用来调节宿主细胞信号的机制的彻底了解将导致对这种寄生虫和其他Apicomplexan寄生虫的更好的治疗。与公共卫生相关：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。预计这项资助的结果将使人们彻底了解弓形虫用来调节宿主细胞信号的机制。这可能会导致对这种寄生虫和其他Apicomplexan寄生虫的更好治疗。

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. PUBLIC HEALTH RELEVANCE: Toxoplasma is an obligate intracellular parasite that can cause serious disease in immunocompromised patients and in the developing fetus. It is expected that the results of this grant will lead to a thorough understanding of the mechanisms Toxoplasma uses to modulate host cell signaling. This could lead to better therapies against this and other Apicomplexan parasites.