Toxoplasma proteins that modulate the host cell

调节宿主细胞的弓形虫蛋白

• 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
• 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

 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(申请人提供)：弓形虫是一种专性细胞内寄生虫，可导致免疫抑制患者和胎儿的严重疾病，以及其他健康人的视力丧失。宿主先天免疫的激活是早期发现肺炎的关键 但弓形虫对先天免疫反应的过度激活也会导致病理性炎症。在之前的资助期间，我们已经确定，在检测到弓形虫感染时激活炎症小体是一种重要的先天免疫防御机制。在这一新的应用中，我们将确定弓形虫激活炎症体和核因子κB转录因子的分子机制，这是激活天然免疫的重要因素。炎性小体是参与白介素1和白介素18产生的多蛋白复合体，白介素1和白介素18是细胞因子，在包括弓形虫在内的许多病原体的免疫反应中发挥重要作用。炎性小体的激活也可以诱导一种称为上睑下垂的快速细胞死亡，这可以消除细胞内病原体复制所需的利基。有两个信号参与了活性IL-1的分泌：1)转录因子NFcaspase B的激活，导致原IL-1的表达；2)胞质受体(称为κ)检测微生物和环境危险信号，导致其与原caspase-1(统称为炎症)一起多聚化。当炎症小体组装时，原caspase-1被自动催化处理，可以诱导下垂，但也可以裂解原-IL-1？和原-IL-18，导致它们随后的分泌。为了配合宿主细胞，弓形虫分别从其颗粒细胞器和致密颗粒细胞器分泌名为ROPS和GRAS的效应分子。我们已经确定弓形虫GRA15可以激活NFkB途径，从而提供信号1。我们还发现，弓形虫激活了Lewis大鼠的NLRP1-炎症小体，导致下垂和抑制弓形虫的生长。除了炭疽致命毒素外，弓形虫是唯一已知的NLRP1-炎症体的其他激活剂。因此，确定决定弓形虫-炎症体相互作用的宿主和寄生虫蛋白是很重要的。在我们的第一个目标中，我们将确定弓形虫GRA15调节NFκB转录因子的确切机制。在我们的第二个目标中，我们将专注于鉴定参与弓形虫激活炎性小体的寄生虫分子。这些先天免疫反应在确定人类对弓形虫病的易感性方面发挥了作用，并对防御许多其他病原体具有重要作用。这项研究的结果将有助于更好地理解弓形虫-先天免疫系统的相互作用，并将为一般情况下NLRP1的激活提供新的见解。这将有助于开发针对弓形虫病和其他病原性疾病的改进治疗方法。