MT VET COBRE PROJECT 1: HOST-PATHOGEN COMMUNICATION IN TOXOPLASMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 弓形虫每年感染150万人，仅次于细菌病原体李斯特菌和沙门氏菌，是美国感染相关死亡的主要原因。 弓形虫对胎儿、接受化疗或器官移植的患者以及艾滋病患者都是危险的。 缓殖子发育最终导致永久性感染，因此，发病率和死亡率在免疫功能低下的患者中是显著的，其中缓殖子-速殖子转换是临床疾病发病机制的基础。 我们已经确定，选定的三取代吡咯将影响人成纤维细胞诱导血管内皮细胞株速殖子进行缓殖子分化后48小时内感染。我们的假设是，这些分子通过调节宿主细胞基因表达诱导缓殖子发育，并且特定的宿主细胞途径提供了寄生虫监测缓殖子发育时间的主要信号。 我们使用DNA微阵列鉴定了80种不同的mRNA表达与诱导的缓殖子发育一致。 这些mRNA的早期分析表明，许多可以直接或间接地与生长调节途径和宿主细胞的增殖状态。 通过实验改变宿主细胞的能力，使得侵入的速殖子被诱导启动缓殖子发育，为研究寄生虫发育提供了新的实验策略。 蛋白质，定义了一个特定的宿主环境的分子特征，这是更多（或更少）有利于缓殖子分化，可以提供一个或多个治疗这种感染的目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Toxoplasma gondii infects 1.5 million human subjects annually and ranks only behind the bacterial pathogens, Listeria and Salmonella, as a leading cause of infection-related death in the US. Toxoplasma can be dangerous to the unborn, to patients undergoing chemotherapy or organ transplant, and to people with AIDS. Bradyzoite development is ultimately responsible for permanent infection and as such, morbidity and mortality is significant in the immunocompromised where bradyzoite-tachyzoite switching underlies the pathogenesis of clinical disease. We have determined that selected trisubstituted pyrroles will affect a human fibroblast to induce VEG-strain tachyzoites to undergo bradyzoite differentiation within 48 h post-infection. Our hypothesis is that these molecules induce bradyzoite development in by modulating host cell gene expression, and that specific host cell pathways provide the primary signal that parasites monitor to time bradyzoite development. We have used DNA microarrays to identify 80 distinct mRNAs expressed in concert with induced bradyzoite development. Early analyses of these mRNAs indicate that many can be directly or indirectly associated with growth regulatory pathways and the proliferative state of the host cell. The ability to experimentally alter the host cell, such that, tachyzoites that invade are induced to initiate bradyzoite development provides new experimental strategies to study parasite development. Proteins that define the molecular features of a specific host environment that is more (or less) conducive to bradyzoite differentiation may provide one or more targets for the treatment of this infection.