Toxoplasma proteins that modulate the host cell

调节宿主细胞的弓形虫蛋白

基本信息

批准号：
8880721
负责人：
JEROEN SAEIJ
金额：
$ 8.47万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880721
关键词：
Acquired Immunodeficiency Syndrome Adult Affect Blindness Candidate Disease Gene Cell Death Cell Line Cells Child Chorioretinitis Cleaved cell Clustered Regularly Interspaced Short Palindromic Repeats Color Cyst Cytoplasmic Granules Data Defense Mechanisms Detection Development Disease Early Diagnosis Enzyme-Linked Immunosorbent Assay Equilibrium Fetus Flow Cytometry Funding Genes Genome Goals Growth Guide RNA Health Human Immune Immune response Immune system Individual Infection Inflammation Inflammatory Response Interferon Type II Interleukin-12 Interleukin-18 Interleukins Knockout Mice Lead Libraries Mediating Molecular Multiprotein Complexes Mus Mutation Names Natural Immunity Organelles Outcome Parasite Control Parasites Pathology Pathway interactions Patients Phenocopy Play Predisposition Process Production Proteins RNA library Rattus Reporter Research Role Signal Transduction Site Testing Time Toxoplasma Toxoplasma gondii Toxoplasmosis Wild Type Mouse anthrax lethal factor base cell type cytokine cytosolic receptor genome editing genome sequencing genome-wide improved in vivo insight loss of function macrophage microbial mutant novel obligate intracellular parasite pathogen procaspase-1 protein complex public health relevance rhoptry transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Toxoplasma gondii is an obligate intracellular parasite that can cause serious disease in immune-suppressed patients and fetuses and vision loss in otherwise healthy individuals. Activation of host innate immunity is crucial for early detection of Toxoplasma but an over-activation of innate immune responses can also lead to pathological inflammation. During the previous funding period we have determined that activation of the inflammasome upon detection of Toxoplasma infection is an important innate immune defense mechanism. In this renewal application we will identify the molecular mechanisms by which Toxoplasma activates the inflammasome and the NFκB transcription factor, which is important for activating innate immunity. Inflammasomes are multiprotein complexes that participate in the production of interleukin (IL)-1ß and IL-18, which are cytokines that play important roles in the immune response to many pathogens, including Toxoplasma. Inflammasome activation can also induce a form of rapid cell death known as pyroptosis, which can remove the niche that intracellular pathogens need for replication. There are two signals involved in the secretion of active IL-1ß: 1) the activation of the transcription factor NFκB, which leads to the expression o pro-IL-1ß and 2) the detection of microbial and environmental danger signals by cytosolic receptors (named NLRs) leading to their multimerization along with pro-caspase-1 (together called the inflammasome). Pro-caspase-1 is auto catalytically processed when the inflammasome is assembled and can induce pyroptosis but also cleave pro-IL-1ß and pro-IL-18 leading to their subsequent secretion. To co-opt the host cell, Toxoplasma secretes effector molecules named ROPs and GRAs from its rhoptry and dense granule organelles, respectively. We have determined that Toxoplasma GRA15 can activate the NFkB pathway and thereby provide signal 1. We have also shown that Toxoplasma activates the Lewis rat NLRP1-inflammasome, which leads to pyroptosis and inhibition of Toxoplasma growth. Besides Anthrax lethal toxin, Toxoplasma is the only known other activator of the NLRP1-inflammasome. It is therefore important to identify the host and parasite proteins that determine Toxoplasma-inflammasome interactions. In our first aim we will determine the exact mechanism by which Toxoplasma GRA15 modulates the NFκB transcription factor. In our second aim we will focus on identifying the parasite molecules involved in inflammasome activation by Toxoplasma. These innate immune responses play a role in determining human susceptibility to toxoplasmosis, and are important for defense against numerous other pathogens. Results from this research should lead to a better understanding of Toxoplasma-innate immune system interactions and will provide novel insights into NLRP1 activation in general. This will help the development of improved treatments against toxoplasmosis and other pathogenic diseases.

描述（由适用提供）：弓形虫Gondii是一种强大的细胞内寄生虫，可能在免疫抑制的患者和胎儿和其他健康个体的视力丧失中引起严重的疾病。宿主先天免疫组织化学的激活对于早期检测至关重要弓形虫，但先天免疫调查的过度激活也会导致病理炎症。在上一个资金期间，我们确定毒质量感染后炎症体的激活是重要的先天免疫范围机制。在这种续签应用中，我们将确定毒质量激活炎症体和NFκB转录因子的分子机制，这对于激活先天免疫力很重要。炎性症是参与白介素（IL）-1ß和IL-18的产生的多蛋白络合物，它们是细胞因子，在包括弓形虫在内的许多病原体的免疫响应中起重要作用。炎性体激活还可以诱导一种称为凋亡的快速细胞死亡形式，可以消除细胞内病原体复制所需的细分市场。主动IL-1ß的分泌有两个信号：1）转录因子NFκB的激活，这导致了o-pro-il-1ß的表达和2）2）检测细胞溶剂受体（命名为NLR）的微生物和环境危险信号，导致其多种植入和pro-caspase-1（称为sublymassome）。当炎性体组装并诱导凋亡时，对催化剂进行催化剂处理，但也可以清除Pro-Il-1ß和Pro-IL-18，从而导致其随后的分泌。为了选择宿主细胞，分别从其步骤和致密的颗粒细胞器中分泌了效应分子。我们已经确定毒质量GRA15可以激活NFKB途径，从而提供信号1。我们还表明，毒品毒素激活了Lewis Rat NLRP1-炎症体，从而导致毒气，并抑制毒质量生长。除了炭疽致命的毒素外，毒素是NLRP1-炎症体的唯一其他已知的激活剂。因此，重要的是要识别决定弓形虫 - 炎症体相互作用的宿主和寄生虫蛋白。在我们的第一个目的中，我们将确定毒品GRA15调节NFκB转录因子的确切机制。在我们的第二个目标中，我们将专注于识别弓形虫激活涉及炎症体激活的寄生虫分子。这些先天的免疫反应在确定人类对弓形虫病的敏感性方面发挥了作用，对于防御许多其他病原体非常重要。这项研究的结果应导致对弓形虫的免疫系统相互作用有更好的了解，并将提供对NLRP1激活的新见解。这将有助于改善针对弓形虫病和其他致病性疾病的治疗方法。