Toxoplasma strain-specific modulation of mouse immune cells

描述（由申请人提供）：弓形虫是一种专性细胞内寄生虫，可导致免疫功能低下患者和发育中的胎儿严重疾病。在欧洲和北美，从人类患者和牲畜中分离出来的大多数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。在老鼠身上，这三种不同的菌株在毒力和其他表型上有很大的不同，有充分的证据表明，在人类身上也是如此。了解这些不同的弓形虫菌株在致病方面的差异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存在的寄生虫引起组织损伤而引起疾病。如果知道不同的弓形虫菌株是如何致病的，以及患者感染的是哪种菌株，那么治疗方法就可以与感染的具体情况相匹配；在某些情况下，抑制免疫反应可能是最好的选择，而在其他情况下，可能需要抗寄生虫剂的积极治疗。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菌株之间调节宿主细胞信号通路的差异在决定疾病结局中起主要作用。因此，该基金的目标是鉴定和表征参与菌株特异性宿主细胞信号通路调节的弓形虫基因产物。我们将首先确定有毒和无毒弓形虫菌株在调节小鼠体内先天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后代来绘制相关弓形虫基因组区域。随后，我们将使用分子遗传学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可能在其他同样生活在膜限制液泡内的顶复合体中被发现，例如，在肝细胞内生长的疟原虫。因此，对弓形虫调节宿主细胞信号的机制的深入了解将有助于更好地治疗弓形虫和其他顶复合体寄生虫。公共卫生相关性：弓形虫是一种专性细胞内寄生虫，可引起免疫功能低下患者和发育中的胎儿的严重疾病。预计这项资助的结果将导致对弓形虫调节宿主细胞信号的机制的透彻理解。这可能会导致更好的治疗方法来对付这种和其他顶复合体寄生虫。

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.