Mobilization of lysosome anti-microbial defenses by the unfolded protein response

通过未折叠的蛋白质反应动员溶酶体抗微生物防御

基本信息

批准号：
8519298
负责人：
Mary O'Riordan
金额：
$ 17.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8519298
关键词：
Abscess Animal Model Anti-Bacterial Agents Anti-Infective Agents Antibiotic Therapy Autophagocytosis Bacteria Bacterial Infections Biology Cell Culture Techniques Cell physiology Cells Cellular Stress Response Chemicals Confined Spaces Cutaneous Cytosol Data Defense Mechanisms Development Endoplasmic Reticulum Garbage Heart Diseases Homeostasis Host Defense Imaging Techniques Immune Infection Inflammatory Inflammatory Response Invaded Lead Lysosomes Malignant Neoplasms Measures Mediating Messenger RNA Microbe Molecular Morbidity - disease rate OmpR protein Oxidases Pathway interactions Peptide Hydrolases Phagocytes Phagocytosis Phagolysosome Play Positioning Attribute Process Production Protein Secretion Proteins RNA Splicing Receptor Signaling Regulation Role Shapes Signal Transduction Site Testing Toll-like receptors Transcriptional Regulation Virulent Yeasts antimicrobial bafilomycin A biological adaptation to stress cytokine endoplasmic reticulum stress immune function inhibitor/antagonist innate immune function killings macrophage man methicillin resistant Staphylococcus aureus mortality novel pathogen programs protein degradation research study response sensor trafficking uptake vacuolar H+-ATPase

项目摘要

DESCRIPTION (provided by applicant): Professional phagocytes play a critical role in anti-microbial defense. Uptake of microbes by phagocytosis results in the formation of a dynamic vesicular compartment, termed the phagolysosome. The phagolysosome physically and functionally defines a critical separation of the microbe from the host cell, allowing the host to target degradative anti-microbial mechanisms to this confined space. We find that bacterial infection triggers the unfolded protein response (UPR), a cellular program associated with ER stress and innate immune function. Activation of the UPR increases the capacity of the cell to degrade proteins, but the mechanisms responsible for this degradation are incompletely understood. Our preliminary studies suggest that UPR activation during bacterial infection results in increased association of methicillin resistant Staphylococcus aureus (MRSA) with the degradative lysosomal compartment and bacterial killing. Inhibition of specific UPR regulators results in decreased association with lysosomes and decreased MRSA killing. The central hypothesis of this proposal is that activation of the UPR in phagocytes results in increased trafficking and degradative capacity of the phagolysosomal network, leading to enhanced degradative, and thus anti-microbial, function. To test this hypothesis, we will (1) measure mobilization of the lysosomal network using physical and functional markers upon activation of the UPR; (2) define the role of the UPR sensors, Ire1, ATF6 and PERK in regulating specific aspects of lysosomal trafficking and function in response to innate immune signals during infection. Regulation of the degradative capacity of the cell by the UPR is a fundamental strategy by which cells can respond to perturbations in the production or secretion of proteins. Our studies now highlight a novel connection between UPR-mediated degradation and anti-microbial function, and will define key druggable targets that shape the macrophage anti-microbial arsenal for development of anti-infective strategies.

描述（由申请人提供）：专业吞噬细胞在抗微生物防御中起着至关重要的作用。通过吞噬作用吸收微生物会导致形成动态囊泡室，称为吞噬体。吞噬体在物理上和功能上定义了微生物与宿主细胞的临界分离，从而使宿主可以将降解性抗微生物机制靶向到这个狭窄的空间。我们发现细菌感染会触发与ER应激和先天免疫功能相关的细胞程序展开的蛋白质反应（UPR）。 UPR的激活增加了细胞降解蛋白质的能力，但是对这种降解的机制却不完全了解。我们的初步研究表明，在细菌感染期间的UPR激活导致甲氧西林抗性金黄色葡萄球菌（MRSA）与降解性溶酶体隔室和细菌杀伤的关联增加。对特定UPR调节剂的抑制导致与溶酶体的关联降低，并降低了MRSA杀伤。该提议的中心假设是，吞噬细胞中UPR的激活导致吞噬溶血体网络的运输和降解能力增加，从而增强了降解性，从而增加了抗菌功能。为了检验这一假设，我们将使用物理和功能标记在UPR激活后使用物理和功能标记来测量溶酶体网络的动员；（2）定义了UPR传感器，IRE1，ATF6和PERK在调节感染过程中先天免疫信号的响应溶酶体运输和功能方面的特定方面的作用。通过UPR调节细胞的降解能力是一种基本策略，细胞可以通过该策略对蛋白质生产或分泌的扰动做出反应。现在，我们的研究重点介绍了UPR介导的降解与抗微生物功能之间的新联系，并将定义关键的可药靶标，该靶标会塑造巨噬细胞抗微生物武库以发展抗感染策略。