Host-pathogen interactions during hospital adaptation of MRSA

MRSA 医院适应期间宿主与病原体的相互作用

• 批准号: 10459365
• 负责人: BO SHOPSIN
• 金额: $ 79.96万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459365
• 关键词: Accounting; Affect; Animal Model; Antibiotic Resistance; Attenuated; Bacteria; Bacterial Genes; Blood Circulation; Categories; Cells; Clinical; Communities; Community Hospitals; Complex; Detection; Disease; Epidemiology; Event; Evolution; Expression Profiling; Frequencies; Genes; Genetic; Genetic Transcription; Genus staphylococcus; Goals; Hospitalization; Hospitals; Human; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Inflammatory; Innate Immune Response; Innate Immune System; Knowledge; Laboratories; Lung; Measures; Mediating; Mediator of activation protein; Metabolism; Minor; Molecular; Mus; Mutation; Nosocomial pneumonia; Outcome; Output; Pathogen detection; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pneumonia; Population; Primary Infection; Production; Regulator Genes; Regulatory Pathway; Respiratory System; Risk; Role; Sampling; Signal Transduction; Source; Staphylococcus aureus infection; System; Systems Biology; Testing; Time; Tissues; Toxin; Vaccines; Variant; Virulence; Virulent; Work; antimicrobial; biomarker development; comparative; cytokine; cytotoxicity; design; genome sequencing; immune function; in vivo; individualized medicine; interest; macrophage; methicillin resistant Staphylococcus aureus; mouse model; mutant; novel; pathogen; preconditioning; pressure; programs; response; screening; success; trait; transcriptome sequencing; uptake; whole genome

PROJECT SUMMARY Our long-term goal is to transform knowledge of nosocomial evolution into successful management strategies to confront the growing problem of methicillin-resistant Staphylococcus aureus (MRSA). Here we focus on understanding the different ways by which community- and hospital-associated MRSA (CA- and HA-MRSA) interact with components of the innate immune system to cause different epidemiology and outcomes of infection. Work by us and others suggests that adaptation of MRSA to hospital conditions often involves an interplay of mutations that coordinately confer antibiotic resistance and attenuate virulence. How the resulting changes affect host–pathogen interactions at the cellular and molecular levels is poorly understood. Given that macrophages are central mediators of MRSA uptake and dissemination, we will identify differential mechanisms governing CA- and HA-MRSA intracellular detection by, and survival in, host macrophages. Our preliminary results indicate that the production of cytolytic toxins, which is repressed in HA-MRSA and enhanced in CA-MRSA, enable intracellular MRSA to overcome the expression of macrophage immunity and enhance pathogen survival. At the same time, attenuated cytolytic activity may be advantageous in certain situations, such as in hospital-associated infections, because suppression of inflammatory activity might avoid detection of the pathogen or limit damage to it by the host immune system. The complexity of the selective forces that drive these traits underscores the need for a comprehensive, systems approach to examine the role of host and pathogen capabilities in determining how MRSA subsets differentially modulate immune responses. Given that host–pathogen interactions are pleotropic and interconnected, analysis of individual genes alone cannot explain the cellular responses to infection, much less the bacterial responses. We leverage the power of systems-level analysis of CA-MRSA, transitional CA-MRSA, and HA-MRSA to understand the interactions between MRSA and macrophages during infection. We will interpret profiling results in the context of measures of pathogen versus host success. These include the fate of intracellular bacteria during infection of macrophages in vitro and in murine models specifically designed to reflect conditions in hospitalized patients (disruption of immune functions permit MRSA strains that lack full virulence to cause infection). We will prepare bacterial mutants of relevant pathways to recreate the capabilities of CA- or HA-MRSA strains. We will also perturb specific networks, both in infected human macrophages and in infected murine models, to identify loci where the pathways can be manipulated. By determining the similarities and differences in the host and pathogen transcriptional programs during macrophage infection, comparative analyses between CA- and HA-MRSA will transform our understanding of the pathogenesis of both forms of MRSA. The output will be a mechanistic understanding of host-pathogen interactions that determine the outcome of MRSA infection. Those findings will provide an analytic framework to help control MRSA.

项目概要 我们的长期目标是将医院演变的知识转化为成功的管理策略 应对日益严重的耐甲氧西林金黄色葡萄球菌 (MRSA) 问题。这里我们重点关注 了解社区和医院相关 MRSA（CA 和 HA-MRSA）的不同方式 与先天免疫系统的组成部分相互作用，导致不同的流行病学和结果 感染。我们和其他人的工作表明，MRSA 适应医院条件通常涉及 突变的相互作用协调地赋予抗生素耐药性并减弱毒力。怎么产生的 人们对细胞和分子水平上宿主与病原体相互作用的影响知之甚少。鉴于 巨噬细胞是 MRSA 摄取和传播的中心介质，我们将识别差异 宿主巨噬细胞对 CA- 和 HA-MRSA 进行胞内检测并在其中存活的机制。我们的 初步结果表明，HA-MRSA 和细胞溶解毒素的产生受到抑制 CA-MRSA 增强，使细胞内 MRSA 能够克服巨噬细胞免疫的表达， 提高病原体的存活率。同时，减弱的细胞溶解活性在某些方面可能是有利的。 情况下，例如在医院相关的感染中，因为抑制炎症活动可能会避免 检测病原体或限制宿主免疫系统对其造成的损害。选择性的复杂性 驱动这些特征的力量强调需要采用全面的系统方法来检查角色 确定 MRSA 子集如何差异调节免疫的宿主和病原体能力 回应。鉴于宿主与病原体的相互作用是多效性且相互关联的，对个体的分析 基因本身无法解释细胞对感染的反应，更不用说细菌的反应了。我们 利用 CA-MRSA、过渡性 CA-MRSA 和 HA-MRSA 的系统级分析能力 了解感染期间 MRSA 和巨噬细胞之间的相互作用。我们将解释分析 结果是在病原体与宿主成功的测量背景下得出的。这些包括细胞内的命运 体外和专门设计用于反映巨噬细胞感染过程的小鼠模型中的细菌 住院患者的情况（免疫功能的破坏导致 MRSA 菌株缺乏完全毒力 从而引起感染）。我们将制备相关途径的细菌突变体，以重建 CA-的能力 或 HA-MRSA 菌株。我们还将扰乱特定的网络，无论是在受感染的人类巨噬细胞还是在 受感染的小鼠模型，以确定可以操纵通路的位点。通过确定相似性 以及巨噬细胞感染期间宿主和病原体转录程序的差异，比较 CA-和 HA-MRSA 之间的分析将改变我们对这两种形式的发病机制的理解 耐甲氧西林金黄色葡萄球菌。输出将是对宿主-病原体相互作用的机械理解，这决定了 MRSA 感染的结果。这些发现将为帮助控制 MRSA 提供一个分析框架。