Bartonella: dissecting niche-specific adaptation in a human pathogen

巴尔通体：剖析人类病原体的生态位特异性适应

• 批准号: 8579795
• 负责人: JANE E KOEHLER
• 金额: $ 44.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579795
• 关键词: AIDS/HIV problem; Alphaproteobacteria; Apical; Arthropod Vectors; Arthropods; Bacillary Angiomatosis; Bacillus (bacterium); Bacteremia; Bacteria; Bartonella; Bartonella quintana; Binding; Blood; Blood Circulation; Blood Vessels; Cancer Patient; Cells; Coxiella; DNA-Directed RNA Polymerase; Data; Elements; Endothelial Cells; Environment; Epithelial Cells; Europe; Excretory function; Feces; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Heart; Heart Valves; Heme; Hemin; Homologous Gene; Human; Human body; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Insecta; Intestines; Iron; Knowledge; Lesion; Lice; Life; Life Cycle Stages; Malignant Neoplasms; Mallophaga; Mediating; Microbial Biofilms; Pathogenesis; Pediculus; Pediculus humanus humanus; Play; Preventive Intervention; Proliferating; Proteins; Proteobacteria; Regulator Genes; Regulon; Research; Role; Sigma Factor; Stress; Structure; Surface; System; Temperature; Testing; Therapeutic Intervention; Transplantation; Trench Fever; Virulence; Virulence Factors; Work; World War I; biological adaptation to stress; cold temperature; environmental change; in vivo; mutant; novel; pathogen; programs; promoter; public health relevance; response; stressor; vector; wound

DESCRIPTION (provided by applicant): Bartonella quintana (BQ) is a gram-negative human pathogen that causes serious and potentially fatal infections, and is the leading cause of culture-negative heart valve infection in the US. BQ also causes persistent bacteremia and fatal illness in immunocompromised individuals with cancer and HIV/AIDS. BQ is transmitted to humans by the body louse; humans become infected when the BQ bacteria in the louse feces are introduced into the louse bite wound by scratching. BQ alternates between two very different niches: the bloodstream of the homeothermic mammalian reservoir (37¿C) and the gut of the poikilothermic arthropod vector (28¿C). Virtually nothing is known about the virulence factors involved in the transition between the host and arthropod vector. However, the arthropod niche is an essential part of the life cycle of BQ, and it is required for infection of humans. To surviv and proliferate, BQ bacteria must adapt rapidly during the shift between these two disparate environments. Such adaptation to environmental changes and stresses are frequently mediated by alternative sigma factor subunits of the RNA polymerase. We found that rpoE, an uncharacterized sigma factor gene homologous to the extracytoplasmic function (ECF) sigma factor of several alpha-proteobacteria, is significantly up-regulated at the 28¿C temperature of the arthropod vector. In addition, rpoE is necessary for colonization of lice by BQ. Thus, BQ appears to have uniquely co-opted the alpha-proteobacterial general stress response system to up-regulate genes at 28¿C to adapt to its vector. Our long-term goal is to delineate the transcriptional program employed by the BQ pathogen to permit survival in the transition to, and within the arthropod niche, with the goal of identifying common regulatory themes and targets with potential applicability to other arthropod-borne bacterial pathogens. The short-term goal, and the focus of this proposal, is to identify the niche-specific genes involved in the transition between the arthropod and human host, and the regulatory network controlling their expression in BQ. The specific aims of this proposal are: 1) to determine the in vivo role of RpoE-directed transcription in colonization of the human body louse by BQ; and 2) to define the BQ RpoE regulon response to louse stressors in vitro, and identify RpoE-responsive promoter elements involved in the BQ human-louse transition. Successful completion of these specific aims will have a positive impact by: 1) identifying factors and regulatory networks that are necessary for pathogen transition between niches; 2) leveraging this knowledge to identify targets for preventive and therapeutic intervention in arthropod-borne pathogens; and 3) elucidating the unexplored and novel utilization of the alpha-proteobacterial ECF15 class of s factors for adaptation by the BQ human pathogen. Collectively, our preliminary data and the research proposed herein represent a new paradigm in sigma factor adaptive response for both the ECF15 s factor field, and the bacterial pathogenesis field.

描述（由适用提供）：Bartonella Quintana（BQ）是一种革兰氏阴性的人类病原体，会引起严重且潜在的致命感染，并且是美国培养性阴性心脏瓣膜感染的主要原因。 BQ还会导致癌症和艾滋病毒/艾滋病患者的持续细菌和致命疾病。 BQ通过身体损失传递给人类；当损失粪便中的BQ细菌通过刮擦引入损伤伤口时，人类就会被感染。两个截然不同的壁ni之间的BQ替代方法：植物热哺乳动物储备（37€）和poikilothermothermic节肢动物矢量的血液（28？c）。实际上，关于宿主和节肢动物向量之间涉及的病毒因素几乎一无所知。但是，节肢动物的小众是BQ生命周期的重要组成部分，它是人类感染所必需的。为了存活和增殖，在这两个不同环境之间的转移期间，BQ细菌必须迅速适应。这种对环境变化和应力的适应经常是由RNA聚合酶的替代Sigma因子亚基介导的。我们发现，在节肢动物载体的28波温度下，RPOE是与几个α-甲状腺细菌的外胞质功能（ECF）Sigma因子同源（ECF）的Sigma因子同源的Sigma因子基因（ECF）Sigma因子。此外，RPOE对于通过BQ定植是必要的。这就是BQ似乎独特地选择了α-细菌蛋白蛋白质应激反应系统，以上调节了28？c的基因以适应其载体。我们的长期目标是描述BQ病原体所携带的转录程序，以允许在过渡到节肢动物的过渡中生存，目的是识别具有对其他节肢动物 - - 元素 - 元素菌病原体的可能适用性的常见调节主题和靶标。短期目标以及该提案的重点是确定节肢动物和人类宿主之间过渡的小众特异性基因，以及控制其在BQ中表达的监管网络。该提案的具体目的是：1）确定RPOE指导转录在BQ丧失人体丧失中的体内作用； 2）为定义BQ RPOE调节体外损失应力源的反应，并识别涉及BQ人甲过渡的RPOE响应启动子元素。这些特定目标的成功完成将产生积极的影响：1）识别壁nikes之间病原体过渡所必需的因素和调节网络； 2）利用这种知识来确定针对节肢动物传播病原体的预防和治疗干预的靶标； 3）阐明了α-细菌ECF15 S类S因子的意外和新颖利用，以通过BQ人病原体适应。总的来说，我们的初步数据和本文提出的研究代表了ECF15 S因子场和细菌发病机场的Sigma因子自适应反应的新范式。