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(申请人提供)：巴尔通氏菌(BQ)是一种革兰氏阴性的人类病原体，可导致严重和潜在的致命感染，是美国培养阴性心脏瓣膜感染的主要原因。BQ还会在患有癌症和艾滋病毒/艾滋病的免疫功能受损的人中造成持续性菌血症和致命疾病。BQ是通过体虱传播给人类的；当虱子粪便中的BQ细菌通过抓挠进入虱子咬伤伤口时，人类就会被感染。BQ在两个非常不同的生态位之间交替：恒温哺乳动物储藏室的血液(37℃)和变温节肢动物媒介的肠道(28℃)。关于寄主和节肢动物媒介之间的转化过程中涉及的毒力因子，几乎一无所知。然而，节肢动物的生态位是BQ生活史中必不可少的一部分，它是人类感染所必需的。为了生存和繁殖，BQ细菌必须在这两个不同环境之间的转变中迅速适应。这种对环境变化和压力的适应通常是由RNA聚合酶的选择性Sigma因子亚基介导的。我们发现，在节肢动物载体的28℃温度下，与几种α-蛋白细菌的胞外胞质功能(ECF)西格玛因子同源的未鉴定的西格玛因子基因rpoE显著上调。此外，rpoE是BQ定植虱子所必需的。因此，BQ似乎独一无二地选择了阿尔法蛋白细菌一般应激反应系统，在28℃上调基因，以适应其载体。我们的长期目标是描绘BQ病原体所使用的转录程序，以允许在向节肢动物生态位的过渡过程中和在节肢动物生态位内存活，目的是确定共同的调控主题和靶标，对其他节肢动物传播的细菌病原体具有潜在的适用性。短期目标，也是这项提议的重点，是确定节肢动物和人类宿主之间转换所涉及的特定生态位基因，以及控制它们在BQ中表达的调控网络。本研究的具体目的是：1)确定RpoE定向转录在BQ对人体虱子定植中的体内作用；2)确定BQ对虱子应激源的RpoE调节子的体外反应，并鉴定参与BQ人虱转变的RpoE响应启动子元件。这些特定目标的成功完成将产生积极的影响，包括：1)确定病原体在生态位之间转换所必需的因子和调控网络；2)利用这一知识确定节肢动物传播病原体的预防和治疗干预的靶标；3)阐明BQ人类病原体适应未探索的和新的S因子类蛋白蛋白细菌ECF15因子的用途。总之，我们的初步数据和这里提出的研究代表了ECF15 S因子领域和细菌致病机制领域的Sigma因子适应性反应的新范式。