P. gingivalis Mediated Evasion Strategies

牙龈卟啉单胞菌介导的逃避策略

基本信息

批准号：
8532592
负责人：
Caroline A Genco
金额：
$ 32.87万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-05 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532592
关键词：
Affect Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Binding Cardiovascular Diseases Cell Culture Techniques Cell Death Cell Line Cells Chronic Cleaved cell Cysteine Protease Disease Endothelial Cells Host Defense Host Defense Mechanism Immune Immune response Immunologic Receptors In Vitro Infection Inflammation Inflammatory Inflammatory Response Intraperitoneal Injections Ligands Lys-gingipain Lysine Magnetic Resonance Imaging Mediating Membrane Modeling Modification Monitor Mus Oral Periodontal Diseases Phosphotransferases Play Porphyromonas gingivalis Prediabetes syndrome Protein Kinase Proteins Proteolysis RIPK2 gene Reporter Reporting Risk Factors Role Signal Transduction Site Specificity Stroke TNFRSF1A gene Term Birth Testing Therapeutic Agents Toll-like receptors United States bone bone loss defense response gingipain human RIPK1 protein in vivo inhibitor/antagonist macrophage mutant novel strategies novel therapeutic intervention oral infection oral pathogen pathogen prevent public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): A number of successful pathogens have evolved mechanisms to evade host defense, thus establishing persistent and chronic infections. A hallmark of chronic infection with the oral pathogen, Porphyromonas gingivalis, is the induction of a chronic inflammatory response. Although membrane- bound innate immune receptors, including Toll-like receptors (TLR), play a role in inflammation in response to P. gingivalis, it i unknown how intracellular host defense mechanisms to this pathogen contribute to persistent infection and resulting in chronic inflammation. We have recently reported on a novel strategy by which P. gingivalis modulates the levels of key intracellular proteins involved in cell death and host defense responses. We demonstrate that the lysine-specific bacterial cysteine protease of P. gingivalis (gingipain K - Kgp) induces the proteolysis of receptor interacting protein kinase 1 (RIPK1) and RIPK2. Our preliminary studies reveal functional consequences of P. gingivalis mediated RIPK degradation on intracellular immune signaling responses. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation. Given the roles of RIPK in TNF-R induced cell activation and sensing of intracellular pathogens, we propose the ability of P. gingivalis to transiently degrade RIPK functions as a mechanism to avoid intracellular innate immune signaling and allows for bacterial persistence within target cells. The following specific Aims will test this hypothesis: Aim 1. To define the functional consequences of Kgp-mediated RIPK degradation on innate immune signaling and bacterial persistence; Aim 2. To characterize the ability of RIPK cleaved products to function in inhibition of NF?B activation; Aim 3. To assess the efficiency of gingipain inhibitos on the inhibition of P. gingivalis-induced chronic inflammation at local sites in a murine model; and Aim 4. To assess the efficiency of gingipain inhibitors on the inhibition of P. gingivalis-induced chronic inflammation at systemic sites in an ApoE-/- murine model. The ability to specifically block Kgp-mediated modification of cellular kinases represents a novel strategy to target bacterial persistence and innate immune signaling within host cells. Successful undertaking of the proposed studies has the potential to identify and validate novel therapeutic interventions that target pathogen evasion mechanisms associated with chronic infection and the resulting inflammatory sequelae.

描述（由申请人提供）：许多成功的病原体具有进化的机制来逃避宿主防御，从而建立了持久性和慢性感染。口腔病原体卟啉单胞菌的慢性感染的标志是诱导慢性炎症反应。尽管膜结合的先天免疫受体（包括收费受体（TLR））在响应牙龈牙周疟原虫的响应中起作用，但我尚不知道该病原体的细胞内宿主防御机制如何导致持续性感染并导致慢性炎症。我们最近报告了一种新型策略，牙龈疟原虫通过该策略调节与细胞死亡和宿主防御反应有关的关键细胞内蛋白质的水平。我们证明，牙龈疟原虫（gingipain k -kgp）的赖氨酸特异性细菌性半胱氨酸蛋白酶诱导受体相互作用蛋白激酶1（RIPK1）和RIPK2的蛋白水解。我们的初步研究揭示了牙龈疟原虫介导的RIPK降解对细胞内免疫信号反应的功能后果。这些研究支持了新兴概念，即病原体介导的慢性炎症性疾病是由特定病原体介导的逃避策略导致低度慢性炎症引起的。鉴于RIPK在TNF-R诱导的细胞活化和细胞内病原体的感知中的作用，我们提出了牙龈疟原虫瞬时降解RIPK的能力，作为避免细胞内的先天免疫信号传导的机制，并允许在靶细胞内进行细菌持久性。以下具体目的将检验以下假设：目的1。定义KGP介导的RIPK降解对先天免疫信号传导和细菌持久性的功能后果；目的2。表征RIPK切割产物在抑制NF？B激活中起作用的能力；目的3。评估牙龈抑制剂对植物模型中局部部位抑制牙龈疟原虫诱导的慢性炎症的效率；和目标4。评估牙龈抑制剂对牙龈疟原虫诱导的慢性炎症在APOE-/ - 鼠模型中的慢性炎症的效率。特异性阻断KGP介导的细胞激酶的修饰的能力代表了靶向细菌持久性和宿主细胞中先天免疫传导的新策略。拟议的研究成功进行的实施有可能识别和验证与慢性感染和产生的炎症后遗症有关的新型治疗干预措施。