Global Transcriptome Analysis of Mucosal Gonoccal Infection

粘膜淋菌感染的全局转录组分析

• 批准号: 9333190
• 负责人: Caroline A Genco
• 金额: $ 67.06万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333190
• 关键词: Address; Antibiotic Resistance; Antibiotics; Antigens; Antimicrobial Resistance; Bacteria; Bacteriophages; Bioinformatics; Categories; Cefixime; Centers for Disease Control and Prevention (U.S.); Cephalosporins; China; Detection; Development; Disease; Drug resistance; Environment; Epithelial Cells; Etiology; FDA approved; Female; Fluoroquinolones; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; Gonorrhea; Human; Hydrogen Peroxide; Immune; In Vitro; Infection; Intervention; Invaded; Irrigation; Morbidity - disease rate; Nature; Neisseria gonorrhoeae; Oxygen; Pathogenesis; Pathogenicity; Pharmacology; Predisposition; Proteins; RNA; Reporting; Resistance; Role; Sampling; Self-Administered; Sexually Transmitted Agents; Southeastern Asia; Specimen; Statistical Data Interpretation; Surface; Swab; Testing; Therapeutic; Treatment Protocols; Urethra; Vaccines; Vaginal Douching; Virulence; Woman; World Health Organization; antimicrobial drug; authority; base; cervicovaginal; cohort; deep sequencing; design; human disease; immunogenicity; in vivo; male; men; microorganism; mouse model; mutant; neutrophil; new therapeutic target; novel; novel therapeutics; pathogen; public health relevance; reproductive tract; resistant strain; response; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a high morbidity disease worldwide with an estimated 106 million cases annually. N. gonorrhoeae infects the male and female genital tract and can often evade host immune mechanisms to persist until antibiotic intervention. The alarming increase in antibiotic resistant strains of N. gonorrhoeae, the often-asymptomatic nature of this disease in women, and the lack of a vaccine directed at crucial virulence determinants, speaks to the urgent need to study this pathogen during natural disease in humans to guide new therapies to treat infection. The studies proposed here are designed to identify gonococcal "in vivo expressed factors" (IVEFs) with the long- term goal to develop these as new therapeutic targets. Our studies have focused on a cohort of subjects attending the National Center for STD Control (NCSTD) in Nanjing, China due to the high level of disease in this region and reports of gonococcal strains with increased resistance. Using urethral and vaginal lavage samples obtained from the Nanjing cohort, together with RNA deep sequencing we were the first to identify genes expressed during natural infection, which were not detected in the corresponding gonococcal strains cultured under in vitro conditions. Within the group of common gonococcal genes detected with high-level expression during natural mucosal infection in men and women, was a group of previously uncharacterized gonococcal phage and hypothetical genes as well as genes encoding antimicrobial resistant determinants. We hypothesize that the gonococcus expresses genes in vivo that have not previously been identified in vitro. Despite differences in the gonococcal transcriptome expressed during natural infection in female and male subjects, common genes can be identified and have the potential to represent new therapeutic targets. We propose the following Aims to address this hypothesis: Aim 1. To define the N. gonorrhoeae transcriptome expressed during in vivo infection of the male and female genital tract and identify gonococcal IVEFs. Aim 2. To define the role of subsets of IVEF in N. gonorrhoeae pathogenesis. The studies proposed in this application are the first to examine the global transcriptome of N. gonorrhoeae during natural mucosal infection and to identify and characterize novel genes expressed in vivo that have not been yet hypothesized to exist.

 描述（由适用提供）：淋病奈瑟氏菌是性传播感染（STI）淋病的灾难性药物，这是全球高发病率疾病，每年估计有1.06亿例病例。 N.淋病感染了雄性和女性生殖道，通常可以逃避宿主的免疫机制，直到抗生素干预为止。淋病猪笼草的抗生素耐药菌菌株的惊人增加，女性通常是这种疾病的性质以及缺乏针对至关重要的病毒确定剂的疫苗，这表明迫切需要研究这种自然疾病期间人类自然疾病的病原体，以引导人类引导新疗法治疗新疗法。此处提出的研究旨在确定淋球菌“体内表达的因素”（IVEF），其长期目标是将其作为新的治疗靶标开发。我们的研究集中在中国南京国家性病控制中心（NCSTD）的一系列受试者，这是由于该地区疾病的高水平以及淋球菌菌株的报道，其耐药性增加。使用从Nanjing队列获得的尿道和阴道灌洗样品，以及RNA深测序，我们是第一个鉴定自然感染中表达的基因，在体外条件下培养的相应的淋球菌菌株中未检测到。在男性和女性自然粘膜感染期间用高水平表达检测到的常见的淋球菌基因中，是一组先前未表征的淋球菌噬菌体和假设基因以及编码抗菌抗性决定剂的基因。我们假设淋球菌在体内表达基因，这些基因以前尚未在体外鉴定出来。尽管在女性和男性受试者的自然感染期间表达的淋球菌转录组差异，但可以鉴定出常见基因，并有可能代表新的治疗靶标。我们提出以下目的旨在解决这一假设：目的1。定义在男性和女性生殖道体内感染期间表达的淋病转录组并识别淋球菌IVEF。目的2。定义IVEF亚群在淋病发病机理中的作用。本应用中提出的研究是第一个检查自然粘膜感染期间淋病链球菌的全局转录组，并识别和表征在体内表达的新基因，这些基因尚未假设存在。