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: 10004561
• 负责人: BO SHOPSIN
• 金额: $ 82.98万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004561
• 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; 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.

项目摘要 我们的长期目标是将对医院进化的知识转变为成功的管理策略 面对日益增长的耐甲氧西林金黄色葡萄球菌（MRSA）的问题。在这里我们关注 了解社区和医院相关的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，以引起不同的流行病学和结果 感染。我们和其他人的工作表明，MRSA适应医院状况通常涉及 协同赋予抗生素耐药性并衰减病毒的突变相互作用。如何产生 变化会影响细胞和分子水平上的宿主 - 病因相互作用。鉴于 巨噬细胞是MRSA吸收和传播的中心介体，我们将确定差异 通过宿主巨噬细胞中的细胞内检测和生存，控制CA-和HA-MRSA的机制。我们的 初步结果表明，在HA-MRSA和 在CA-MRSA中增强，使细胞内MRSA克服巨噬细胞免疫的表达和 增强病原体的存活。同时，衰减的溶溶活性在某些方面可能是有利的 情况，例如与医院相关的感染中的情况，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损害。选择性的复杂性 推动这些特征的力量强调了需要全面的系统方法来检查角色的需求 宿主和病原体能力在确定MRSA子集如何不同调节免疫方面的能力 回答。鉴于宿主 - 病原体相互作用是多余的和相互联系的，请分析个体 仅基因无法解释细胞对感染的反应，更不用说细菌反应了。我们 将CA-MRSA，过渡性CA-MRSA和HA-MRSA的系统级分析的功能 了解感染过程中MRSA与巨噬细胞之间的相互作用。我们将解释分析 导致病原体与宿主成功的衡量标准。这些包括细胞内的命运 巨噬细胞在体外和鼠模型中的感染期间细菌专门旨在反映 住院患者的状况（免疫功能的破坏允许缺乏全病毒的MRSA菌株 引起感染）。我们将准备相关途径的细菌突变体，以重现CA-的能力 或HA-MRSA菌株。我们还将在受感染的人类巨噬细胞和中扰动特定网络 感染的鼠模型，以确定可以操纵途径的局部。通过确定相似之处 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两种形式的发病机理的理解 MRSA。输出将是对确定宿主 - 病原体相互作用的机械理解 MRSA感染的结果。这些发现将提供一个分析框架来帮助控制MRSA。