Lysosomal maturation during periodontal infections

描述（由申请人提供）：牙周炎是一种慢性炎症性疾病，由红色复合牙周病原体引起的多种微生物感染引起，其中最具特征的是牙龈卟啉单胞菌（P.g.）。为了在不利的宿主环境中建立慢性感染，病原体设计了它们逃避或破坏旨在消除它们的宿主防御机制的机制，其中一种机制是溶酶体介导的降解。我们认为牙龈卟啉单胞菌通过劫持自噬体途径在巨噬细胞中创建保护性细胞内生态位来破坏吞噬溶酶体降解。具体而言，我们将检验自噬体形成的上调对于牙龈卟啉单胞菌在巨噬细胞中的存活至关重要并且需要MREG介导的溶酶体成熟的假设。在具体目标1中，我们将检验P. g.螯合到自噬体中，并提供保护免于溶酶体降解。在具体目标2中，我们重点讨论了P.G.进入巨噬细胞有助于其运输概况和持久性。具体目标3 将集中在LPS-TLR介导的信号通路有助于溶酶体成熟，因为它涉及自噬。 公共卫生相关性：作为免疫系统的哨兵，巨噬细胞的功能是通过降解过程消除病原体，作为宿主免疫应答的一部分。许多细菌病原体破坏这些过程，使其持续存在，存活，并在某些情况下复制，从而使其传播，从而导致全身性疾病。在这些研究中，我们将研究牙周病原体牙龈卟啉单胞菌通过隔离进入非降解区室来逃避宿主防御机制的分子机制。这些隔室的形成需要一种新的溶酶体（降解）功能调节剂，称为黑素调节素。了解黑素调节蛋白如何促进病原体降解将使我们能够开发治疗方法来增强慢性感染期间的溶酶体功能。

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. PUBLIC HEALTH RELEVANCE: As sentinels of the immune system, macrophages function to eliminate pathogens through degradative processes as part of the host immune response. Numerous bacterial pathogens subvert these processes to persist, survive and in some cases replicate allowing for their dissemination thereby contributing to systemic disease. In these studies we will investigate the molecular mechanism by which a perio-pathogen, P.gingivalis evades the host defense mechanism by sequestration into none degradative compartments. Formation of these compartments requires a novel regulator of lysosome (degradative) function called melanoregulin. Understanding how melanoregulin contributed to pathogen degradation will allow us to develop therapeutic approaches to enhancing lysosome function during chronic infection.