The role of redox sensing in Listeria monocytogenes pathogenesis

氧化还原传感在单核细胞增生李斯特菌发病机制中的作用

• 批准号: 9761447
• 负责人: Michelle Lynne Reniere
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761447
• 关键词: Address; Aerobic; Animals; Attenuated; Biological; Cell Respiration; Cells; Chemicals; Critical Pathways; Cues; Cytosol; Data; Defect; Disease; Environment; Gene Expression; Genes; Genetic; Genetic Transcription; Gram-Positive Bacteria; Growth; Host Defense; In Vitro; Infection; Invaded; Investigation; Listeria monocytogenes; Liver; Measures; Mediating; Modeling; Modification; Monitor; Morbidity - disease rate; Octodon; Operon; Organ; Orphan; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pathway interactions; Phagosomes; Phenotype; Protein Family; Regulation; Regulon; Reporter; Role; Signal Transduction; Spleen; Stress; Study models; Suppressor Mutations; Testing; Tissues; Virulence; antimicrobial; experimental study; in vivo; inhibitor/antagonist; macrophage; monolayer; mortality; mouse model; mutant; pathogen; pathogenic bacteria; programs; promoter; response; stressor; tool; transcription factor

PROJECT SUMMARY Intracellular pathogens account for a significant amount of morbidity and mortality world-wide. Here, the model facultative intracellular pathogen Listeria monocytogenes (Lm) will be used to investigate how bacterial pathogens recognize and adapt to the host environment. Previous studies suggested a model in which specific alterations in the redox environment are one of the biological cues detected by intracellular pathogens during infection as a mechanism to sense their localization and regulate genes accordingly. Specifically, we identified the redox-responsive transcriptional regulator SpxA1 as essential for aerobic growth in vitro and critical for Lm virulence. Preliminary data revealed that SpxA1 regulates hundreds of genes in vitro and in vivo. These results have set the stage for investigations into the specific genes that are required in each distinct growth environment. Experiments proposed in Aim 1a will identify the genes that are required for Lm aerobic growth in vitro, while Aim 1b and 1c will define the SpxA1-dependent genes required for pathogenesis. Experiments described in Aim 2 will develop reporter strains with which to monitor SpxA1 activity and will apply these to define the host signals that activate SpxA1 in vivo. Professional pathogens, such as Lm, have evolved to resist or evade host-derived antimicrobial factors that target invading pathogens. We will use SpxA1-mediated transcriptional adaptation as a sensitive readout with which to investigate these host defenses. Results from these studies will identify the host cell stressors that are encountered during infection and the corresponding Lm transcriptional response that is required for pathogenesis. A thorough understanding of the signaling cascades that are activated during infection and the host cues that stimulate these pathways may reveal fundamental features of the host cytosol that intracellular bacterial pathogens have evolved to detect.

项目摘要 细胞内病原体占世界范围内发病率和死亡率的显著量。这里 模式兼性细胞内病原体单核细胞增生李斯特菌（Lm）将被用来研究如何细菌 病原体识别并适应宿主环境。以前的研究提出了一个模型，其中特定的 氧化还原环境的改变是细胞内病原体检测到的生物学线索之一， 感染作为一种机制来感知它们的定位并相应地调节基因。具体来说，我们发现 氧化还原反应转录调节因子SpxA1对体外需氧生长和Lm至关重要 毒性。初步数据显示，SpxA1在体外和体内调节数百个基因。这些结果 为研究每种不同生长所需的特定基因奠定了基础 环境 目标1a中提出的实验将鉴定Lm体外需氧生长所需的基因， 而Aim 1b和1c将定义致病所需的SpxA1依赖基因。述实验 目标2将开发报告菌株，用于监测SpxA 1活性，并将应用这些菌株来定义 在体内激活SpxA1的宿主信号。专业的病原体，如Lm，已经进化到抵抗或逃避 宿主来源的抗微生物因子，靶向入侵的病原体。我们将使用SpxA1介导的转录 适应作为一个敏感的读出与调查这些主机防御。这些研究的结果将 鉴定在感染过程中遇到的宿主细胞应激因子和相应的Lm转录 发病机制所需的反应。对信号级联的透彻理解 在感染过程中激活，刺激这些途径的宿主线索可能揭示了 细胞内细菌病原体进化出的宿主细胞质。