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（由申请人提供）：弓形虫是一种专性细胞内寄生虫，可导致免疫抑制的患者和胎儿患严重疾病，并导致健康个体视力丧失。宿主先天免疫的激活对于早期发现弓形虫至关重要。弓形虫和先天免疫反应的过度激活也可能导致病理性炎症。在之前的资助期间，我们已经确定，检测到弓形虫感染时炎症小体的激活是一种重要的先天免疫防御机制。弓形虫激活炎症小体和 NFκB 转录因子的分子机制，这对于激活先天免疫非常重要。炎症小体是参与产生的多蛋白复合物。白细胞介素 (IL)-1ß 和 IL-18 是细胞因子，在许多病原体（包括弓形虫）的免疫反应中发挥重要作用，炎症小体激活还可诱导一种称为细胞焦亡的快速细胞死亡形式，从而消除微环境。细胞内病原体复制需要两个信号参与活性 IL-1ß 的分泌：1) 转录因子 NFκB 的激活，从而导致 o 的表达。 pro-IL-1ß 和 2) 通过胞质受体（称为 NLR）检测微生物和环境危险信号，导致其与 pro-caspase-1（统称为 Pro-caspase-1）发生多聚化，并进行自动催化处理。当炎症小体组装时，可以诱导细胞焦亡，但也会裂解 pro-IL-1ß 和 pro-IL-18，导致其随后分泌。弓形虫与宿主细胞合作，分别从其棒状细胞器和致密颗粒细胞器中分泌名为 ROP 和 GRA 的效应分子。我们已经确定，弓形虫 GRA15 可以激活 NFkB 通路，从而提供信号 1。我们还表明，弓形虫可以激活 NFkB 通路。 Lewis 大鼠 NLRP1 炎症小体，可导致细胞焦亡并抑制弓形虫生长，此外还可以致命的炭疽病。弓形虫是唯一已知的 NLRP1 炎症小体激活剂，因此鉴定决定弓形虫炎症小体相互作用的宿主和寄生虫蛋白非常重要。我们的第一个目标是确定弓形虫 GRA15 调节 NFκB 的确切机制。在我们的第二个目标中，我们将重点鉴定参与弓形虫炎症体激活的寄生虫分子。 NLRP1 在确定人类对弓形虫病的易感性方面发挥着重要作用，并且对于防御许多其他病原体也很重要。这项研究的结果应该有助于更好地了解弓形虫与先天免疫系统的相互作用，并将为 NLRP1 激活提供新的见解。开发针对弓形虫病和其他致病性疾病的改进疗法。