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）：许多成功的病原体已经进化出逃避宿主防御的机制，从而建立持续性和慢性感染。口腔病原体牙龈卟啉单胞菌慢性感染的一个标志是诱导慢性炎症反应。尽管膜结合先天免疫受体，包括 Toll 样受体 (TLR)，在牙龈卟啉单胞菌引起的炎症反应中发挥作用，但尚不清楚针对这种病原体的细胞内宿主防御机制如何导致持续感染并导致慢性炎症。我们最近报道了一种新策略，牙龈卟啉单胞菌通过该策略调节参与细胞死亡和宿主防御反应的关键细胞内蛋白质的水平。我们证明牙龈卟啉单胞菌的赖氨酸特异性细菌半胱氨酸蛋白酶 (gingipain K - Kgp) 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卟啉单胞菌介导的 RIPK 降解对细胞内免疫信号反应的功能影响。这些研究支持了新出现的概念，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的，导致低度慢性炎症。鉴于 RIPK 在 TNF-R 诱导的细胞激活和细胞内病原体感知中的作用，我们提出牙龈卟啉单胞菌短暂降解 RIPK 功能的能力，作为避免细胞内先天免疫信号传导并允许细菌在靶细胞内持久存在的机制。以下具体目标将检验这一假设：目标 1. 定义 Kgp 介导的 RIPK 降解对先天免疫信号和细菌持久性的功能影响；目标 2. 表征 RIPK 裂解产物抑制 NF?B 激活的能力；目标 3. 在小鼠模型中评估牙龈蛋白酶抑制剂对抑制牙龈卟啉单胞菌引起的局部慢性炎症的效率；目的 4. 在 ApoE-/- 小鼠模型中评估牙龈蛋白酶抑制剂抑制牙龈卟啉单胞菌诱导的全身部位慢性炎症的效率。特异性阻断 Kgp 介导的细胞激酶修饰的能力代表了一种针对宿主细胞内细菌持久性和先天免疫信号传导的新策略。成功开展拟议的研究有可能确定和验证针对与慢性感染及其引起的炎症后遗症相关的病原体逃避机制的新型治疗干预措施。