Lysosomal maturation during periodontal infections

牙周感染期间溶酶体的成熟

• 批准号: 9042338
• 负责人: Kathleen Boesze-Battaglia
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-12 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042338
• 关键词: Agonist; Autophagocytosis; Autophagosome; Bacteria; Cell surface; Cells; Cholesterol; Chronic; Complex; Degradation Pathway; Disease; Ensure; Environment; Host Defense; Host Defense Mechanism; Immune response; Immune system; Infection; Inflammation; Inflammatory; Link; Lipids; Lysosomes; Mediating; Membrane Microdomains; Microbe; Molecular; Monitor; Myelogenous; Pathway interactions; Periodontal Infection; Periodontitis; Phagolysosome; Phagosomes; Porphyromonas gingivalis; Process; Proteins; Role; Sentinel; Signal Pathway; Sorting - Cell Movement; Systemic disease; Testing; Therapeutic; Up-Regulation; Vesicle; base; design; macrophage; novel; pathogen; periopathogen; trafficking; uptake

DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease that is driven by polymicrobial infection by red-complex periodontal pathogens, the best characterized of which is P. gingivalis (P.g.). To establish chronic infection in hostile host environments pathogens devise mechanisms by which they evade or subvert host defense mechanisms designed to eliminate them, one such mechanism is lysosome mediated degradation. We propose that P. gingivalis subverts phagolysosome degradation by hijacking the autophagosomal pathway to create a protective intracellular niche in macrophages. Specifically, we will test the hypothesis that upregulation of autophagosome formation is critical for P. gingivalis survival in macrophages and requires MREG mediated lysosomal maturation. In specific aim 1 we will test the hypothesis that P. g. sequesters into autophagosomes and confers protection from lysosomal degradation. In specific aim 2 we focus on how the mode of P. g. entry into macrophages contributes to its trafficking profile and persistence. Specific aim 3 will focus on the LPS-TLR mediated signaling pathways contributing to lysosome maturation as it relates to autophagy.

描述(申请人提供)：牙周炎是一种慢性炎症性疾病，是由红色复合体牙周病原体引起的多菌感染所致，最具特点的是牙周炎假单胞菌。为了在敌对的宿主环境中建立慢性感染，病原体设计了一种机制，通过这种机制来逃避或颠覆旨在消除它们的宿主防御机制，其中一种机制是溶酶体介导的降解。我们认为，牙龈假单胞菌通过劫持自噬小体途径，在巨噬细胞中创建保护性的细胞内生态位，从而颠覆吞噬酶体的降解。具体地说，我们将检验这一假设，即自噬小体的形成上调对于牙龈假单胞菌在巨噬细胞中的生存至关重要，并需要MREG介导的溶酶体成熟。在特定的目标1中，我们将检验P.G.隔离进入自噬小体并保护其免受溶酶体降解的假设。在具体目标2中，我们重点研究P.G.进入巨噬细胞的模式如何有助于其运输概况和持久性。具体目标3 将集中在与自噬相关的有助于溶酶体成熟的内毒素-TLR介导的信号通路。

项目成果

A Journey of Cytolethal Distending Toxins through Cell Membranes.

• DOI: 10.3389/fcimb.2016.00081
• 发表时间: 2016
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Boesze-Battaglia K;Alexander D;Dlakić M;Shenker BJ
• 通讯作者: Shenker BJ

Blockade of the PI-3K signalling pathway by the Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces macrophages to synthesize and secrete pro-inflammatory cytokines.

伴随放线菌聚集菌细胞致死膨胀毒素阻断 PI-3K 信号通路，诱导巨噬细胞合成和分泌促炎细胞因子。

• DOI: 10.1111/cmi.12299
• 发表时间: 2014
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Shenker,BruceJ;Walker,LisaP;Zekavat,Ali;Dlakić,Mensur;Boesze-Battaglia,Kathleen
• 通讯作者: Boesze-Battaglia,Kathleen

Aggregatibacter actinomycetemcomitans cytolethal distending toxin activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines.

放线菌聚集菌致死膨胀毒素可激活人巨噬细胞中的 NLRP3 炎症小体，导致促炎细胞因子的释放。

• DOI: 10.1128/iai.03132-14
• 发表时间: 2015
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Shenker,BruceJ;Ojcius,DavidM;Walker,LisaP;Zekavat,Ali;Scuron,MonikaDamek;Boesze-Battaglia,Kathleen
• 通讯作者: Boesze-Battaglia,Kathleen

The Cytolethal Distending Toxin Contributes to Microbial Virulence and Disease Pathogenesis by Acting As a Tri-Perditious Toxin.

• DOI: 10.3389/fcimb.2016.00168
• 发表时间: 2016
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Scuron MD;Boesze-Battaglia K;Dlakić M;Shenker BJ
• 通讯作者: Shenker BJ