The Role of SPARC during Toxoplasma infection in the Brain

SPARC 在大脑弓形虫感染过程中的作用

基本信息

批准号：
8230524
负责人：
Emma H Wilson
金额：
$ 19万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230524
关键词：
Acute Affect Area Behavior Binding Biological Models Brain Brain region Cell physiology Cells Chronic Clinical Cysteine Data Deposition Development Developmental Process Encephalitis Equilibrium Europe Extracellular Matrix Fiber Generations Glycoproteins Human Image Immigration Immune Immune response Immunity Immunocompetent Immunocompromised Host Immunohistochemistry Immunologic Surveillance In Vitro Individual Infection Infection Control Inflammation Inflammatory Response Investigation Kinetics Lead Leukocytes Limb structure Measures Mediating Mus Neurodegenerative Disorders Paralysed Parasites Pathogenesis Pathology Peripheral Phase Predisposition Prevalence Principal Investigator Production Property Proteins Regulation Research Reticulum Role Site South America T-Cell Activation T-Lymphocyte Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis Travel Up-Regulation angiogenesis cell motility chemokine cytokine immunopathology in vivo migration mind control novel novel strategies pathogen prevent programs public health relevance research study response two-photon

项目摘要

DESCRIPTION (provided by applicant): Historically the brain was considered an immune-privileged site with little immune- surveillance. We now understand that there is continuous surveillance but that inflammatory responses need to be tightly controlled. Although the mechanisms of this control have been extensively researched the focus has been primarily on the entry of cells and less about the control of inflammation once present in the brain. Toxoplasma gondii is one of the most common human infections in the world with prevalence rates in the USA at 10-30% and with 80% of people infected in parts of Europe and South America. This protozoan parasite leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency as demonstrated in immune-compromised individuals who succumb to Toxoplasmic encephalitis. Yet there is no apparent pathology related to this continuous presence of inflammation in the brain. Thus, T. gondii leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. This enables investigations into the mechanisms that achieve a well-balanced immune response in the CNS. This proposal investigates the control of T cell migration within the brain during infection. Recent studies of ours have demonstrated that following infection; the presence of a reticular network is formed on which T cells migrate. To elucidate the mechanism involved in this migration experiments will be conducted looking at a secreted glycoprotein called "secreted protein acidic and rich in cysteine" (SPARC). This molecule has been associated with developmental processes in the CNS, extracellular matrix deposition and increased cell migration in the periphery, however has not previously been demonstrated during inflammatory responses in the brain. Following Toxoplasma infection there is a significant increase in SPARC in the CNS associated with parasites and inflammation. This proposal tests the hypothesis that SPARC is necessary and facilitates leukocyte migration in the brain during the immune response to Toxoplasma. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to counter the inflammation that is prevalent and causative in many neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: This proposal investigates the regulation of the inflammatory response in the brain during Toxoplasma infection. This is one of the most common human pathogens however, in the absence of an appropriate immune response can lead to fatal encephalitis. Understanding immune regulation in the brain during Toxoplasma infection, in addition to controlling infection in the brain, may provide novel mechanisms to counter inflammation that is prevalent during neurodegenerative diseases.

描述（由申请人提供）：从历史上看，大脑被认为是一个免疫监测的免疫部位的免疫部位。我们现在了解到有持续的监视，但是炎症反应需要严格控制。尽管该对照的机制已经进行了广泛的研究，但焦点主要是在细胞的进入，而不是大脑中存在的炎症的控制。弓形虫弓形虫是世界上最常见的人类感染之一，在美国的患病率为10-30％，其中80％的人在欧洲和南美的部分地区感染。这种原生动物的寄生虫导致中枢神经系统的慢性感染，在大脑中需要连续的炎症反应，以维持潜伏期，如在免疫受损的个体中所证明的，这些个体屈服于弓形虫性脑炎。然而，与大脑中炎症的连续存在没有明显的病理。因此，Gondii链球菌在大脑中产生了足够鲁棒的免疫反应，可以保护寄生虫，但受到足够控制以防止免疫病理学。这使得对CNS中实现均衡免疫反应的机制进行了研究。该提案调查了感染过程中大脑内T细胞迁移的控制。对我们的最新研究表明，感染后。形成了T细胞迁移的网络网络的存在。为了阐明该迁移实验所涉及的机制，将对一种分泌的糖蛋白进行，称为“分泌的蛋白质酸性，富含半胱氨酸”（SPARC）。该分子与中枢神经系统的发育过程，细胞外基质沉积和周围细胞迁移增加有关，但是以前在大脑炎症反应中尚未证明。随后，弓形虫感染与寄生虫和炎症有关的中枢神经系统中的SPARC显着增加。该提案检验了以下假设：SPARC是必要的，并促进了对弓形虫的免疫反应期间的白细胞迁移。了解外围细胞是如何针对感染部位的，并且仍然可以预防中枢神经系统的免疫病理学与控制影响大脑的感染病原体直接相关。此外，这也可能导致新的机制来应对许多神经退行性疾病中普遍存在和病变的炎症。公共卫生相关性：该提案调查了弓形虫感染期间大脑炎症反应的调节。但是，这是最常见的人类病原体之一，在没有适当的免疫反应的情况下，可能导致致命性脑炎。除了控制大脑感染外，了解弓形虫感染期间大脑中的免疫调节还可能提供新的机制来抵抗神经退行性疾病期间普遍存在的炎症。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Visualizing chemokine-dependent T cell activation and migration in response to central nervous system infection.

DOI：
10.1007/978-1-62703-426-5_11
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Carson, Monica J;Wilson, Emma H
通讯作者：
Wilson, Emma H

Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation.

DOI：
10.1186/1742-2094-9-77
发表时间：
2012-04-25
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Noor S;Wilson EH
通讯作者：
Wilson EH

GLT-1-Dependent Disruption of CNS Glutamate Homeostasis and Neuronal Function by the Protozoan Parasite Toxoplasma gondii.

DOI：
10.1371/journal.ppat.1005643
发表时间：
2016-06
期刊：
PLoS pathogens
影响因子：
6.7
作者：
David CN;Frias ES;Szu JI;Vieira PA;Hubbard JA;Lovelace J;Michael M;Worth D;McGovern KE;Ethell IM;Stanley BG;Korzus E;Fiacco TA;Binder DK;Wilson EH
通讯作者：
Wilson EH

Role of Chemokines and Trafficking of Immune Cells in Parasitic Infections.