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: 9979739
• 负责人: Michelle Lynne Reniere
• 金额: $ 36.58万
• 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/9979739
• 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 细胞内病原体占全世界的大量发病率和死亡率。在这里， 模型辅助细胞内病原体单核细胞增生李斯特菌（LM）将用于研究细菌如何 病原体识别并适应宿主环境。先前的研究提出了一个模型 氧化还原环境中的改变是在细胞内病原体检测到的生物提示之一 感染是一种感知其定位并相应调节基因的机制。具体来说，我们确定了 氧化还原响应的转录调节剂SPXA1对于有氧生长体外至关重要，对于LM至关重要 毒力。初步数据表明，SPXA1在体外和体内调节数百个基因。这些结果 已经为调查每个不同生长所需的特定基因奠定了基础 环境。 AIM 1A中提出的实验将确定体外LM有氧生长所需的基因， 而AIM 1B和1C将定义发病机理所需的SPXA1依赖性基因。描述的实验 在AIM 2中，将开发记者菌株来监视SPXA1活动，并将其应用于定义 在体内激活SPXA1的宿主信号。 LM等专业病原体已进化为抵抗或逃避 靶向入侵病原体的宿主衍生的抗菌因子。我们将使用SPXA1介导的转录 适应作为一种敏感读数，可以研究这些主机防御。这些研究的结果将 确定感染过程中遇到的宿主细胞应激源和相应的LM转录 发病机理所需的反应。对信号级联的透彻理解 在感染过程中激活和刺激这些途径的宿主提示可能揭示 细胞内细菌病原体的宿主细胞质已经进化为检测。