The Role and Regulation of Extracellular Proteases in Staphylococcus aureus

金黄色葡萄球菌胞外蛋白酶的作用及调控

基本信息

批准号：
9978697
负责人：
Lindsey Neil Shaw
金额：
$ 42.96万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-08 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978697
关键词：
Animals Biochemical Biology Blood Cessation of life Cleaved cell Clinical Communicable Diseases Community Hospitals Data Disease Enzymes Etiology Event Future Generations Gene Expression Regulation Glare Human Immune Evasion Impairment In Vitro Individual Infection Knowledge Learning Leukocytes Mediating Mediator of activation protein Molecular Multi-Drug Resistance Nosocomial Infections Organism Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Phagocytosis Process Production Proteins Proteolysis Proteomics Publishing Regulation Resistance Resort Role Staphylococcus aureus Staphylococcus aureus infection System Techniques Therapeutic United States Virulence Virulence Factors Virulent Work attenuation base defined contribution emerging antibiotic resistance extracellular fitness frontier human disease in vivo insight methicillin resistant Staphylococcus aureus mortality novel nutrition pathogen pathogenic bacteria response stem

项目摘要

Abstract A number of studies performed by ourselves and others have investigated the contribution of S. aureus extracellular proteases to disease causation. Until recently, these data proved inconclusive, however work by our group has definitively shown that secreted protease are key mediators of S. aureus disease. Their role appears to be biphasic as: i) Secreted protease deletion leads hypervirulence in infected animals; whilst ii) A complete protease-null strain has impaired survival in human blood, decreased resistance to phagocytosis, increased sensitivity to AMPs and impaired ability for dissemination and/or survival during infection. An explanation for these findings stems from their differing roles, and substrates, during infection. Specifically, the enhanced mortality is driven by an increased abundance of virulence factors, which exist unchecked upon secreted protease deletion. Conversely, the virulence attenuation is mediated by these enzymes attacking the host, cleaving proteins that facilitate nutrition, immune evasion, and dissemination. However, despite this, much remains unknown about how these enzymes are regulated, how they themselves regulate infection, and how they enhance the fitness of S. aureus in vivo. To fill in these gaps we will explore: 1. Regulation by Secreted Proteases During S. aureus Infection. We currently do not know which proteases cleave which virulence factors, or how this influences the progression of infection. As such, in this aim we will connect in vitro virulence factor proteolysis to the pathogenic potential of S. aureus in vivo. 2. The Regulation of Secreted Proteases During S. aureus Infection. Although secreted proteases are produced alongside virulence factors, their synthesis must be (and indeed is) tightly controlled, so as to tailor virulence factor abundance during disease causation. Accordingly, in this aim we will fill in major knowledge gaps regarding secreted protease regulation in vitro, and connect this to what happens in vivo. 3. The Role of Secreted Proteases During S. aureus Infection. The next frontier of protease biology in the context of pathogenic bacteria is an understanding of the host degradome (the complete set of host proteins cleaved by bacterial proteases). Therefore, in this aim we will use cutting edge proteomic techniques to gain insight into the infectious process, and interaction of host with pathogen. Through these studies we will define specific pathways that directly govern S. aureus disease, providing a unique and detailed insight into the molecular events that occur during infection. This will produce key findings regarding S. aureus pathogenesis that has potential to be used for the future generation of novel anti-virulence based therapeutics.

抽象的我们自己和其他人进行的许多研究调查了S的贡献。金黄色金黄色细胞外蛋白酶致病。直到最近，这些数据还没有定论，但是，我们小组的工作明确表明，分泌的蛋白酶是金黄色葡萄球菌。它们的作用似乎是双相的：i）分泌的蛋白酶缺失线索感染动物的过度投资； ii）完整的蛋白酶无菌株的生存障碍在人类血液中，对吞噬作用的抵抗力降低，对AMP的敏感性增加并受损感染过程中传播和/或生存的能力。这些发现词根的解释在感染过程中的不同角色和底物。具体而言，增强的死亡率是受毒力因素的丰富性增加而驱动，而这些因素的存在于分泌蛋白酶删除。相反，毒力衰减是由这些酶介导的攻击宿主，裂解促进营养，免疫逃避和传播的蛋白质。然而，尽管如此，这些酶如何受到调节，如何它们本身调节感染，以及如何增强金黄色葡萄球菌在体内的适应性。填写我们将探讨这些差距：1。金黄色葡萄球菌感染期间分泌的蛋白酶调节。我们目前不知道哪些蛋白酶裂解了哪些毒力因素或这如何影响感染的进展。因此，在此目的中，我们将连接体外毒力因子蛋白水解体内金黄色葡萄球菌的致病潜力。 2。在金黄色葡萄球菌感染。尽管分泌的蛋白酶与毒力因子一起产生，但它们合成必须是（并且确实是）严格控制，以便量身定制毒力因子丰度疾病因果关系。因此，在此目标中，我们将填补有关的主要知识空白分泌的蛋白酶在体外调节，并将其连接到体内发生的情况。 3。金黄色葡萄球菌感染期间的分泌蛋白酶。蛋白酶生物学的下一个领域致病细菌的背景是对宿主降解组的理解（完整的一组宿主蛋白被细菌蛋白酶裂解）。因此，在此目标中，我们将使用最前沿蛋白质组学技术可深入了解感染过程，并与宿主的相互作用病原。通过这些研究，我们将定义直接控制金黄色葡萄球菌的特定途径疾病，为在感染。这将产生有关金黄色葡萄球菌发病机理的关键发现用于基于新型抗病毒疗法的未来一代。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Colorimetric assays for the rapid and high-throughput screening of antimicrobial peptide activity against diverse bacterial pathogens.

用于快速、高通量筛选针对不同细菌病原体的抗菌肽活性的比色测定。

DOI：
10.1016/bs.mie.2021.10.008
发表时间：
2022
期刊：
Methods in enzymology
影响因子：
0
作者：
Allen,JessieL;Kennedy,SarahJ;Shaw,LindseyN
通讯作者：
Shaw,LindseyN

Unraveling the Impact of Secreted Proteases on Hypervirulence in Staphylococcus aureus.

DOI：
10.1128/mbio.03288-20
发表时间：
2021-02-23
期刊：
mBio
影响因子：
6.4
作者：
Gimza BD;Jackson JK;Frey AM;Budny BG;Chaput D;Rizzo DN;Shaw LN
通讯作者：
Shaw LN

The novel two-component system AmsSR governs alternative metabolic pathway usage in Acinetobacter baumannii.

DOI：
10.3389/fmicb.2023.1139253
发表时间：
2023
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
通讯作者：

Identification of a Novel Polyamine Scaffold With Potent Efflux Pump Inhibition Activity Toward Multi-Drug Resistant Bacterial Pathogens.

DOI：
10.3389/fmicb.2018.01301
发表时间：
2018
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
Fleeman RM;Debevec G;Antonen K;Adams JL;Santos RG;Welmaker GS;Houghten RA;Giulianotti MA;Shaw LN
通讯作者：
Shaw LN

An Ex Vivo Model for Assessing Growth and Survivability of Staphylococcus aureus in Whole Human Blood.

用于评估人全血中金黄色葡萄球菌生长和生存能力的离体模型。