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（由申请方提供）：淋病奈瑟菌是性传播感染（STI）淋病的病原体，这是一种高发病率疾病，全球每年估计有1.06亿例病例。N.淋病感染男性和女性生殖道，并且通常可以逃避宿主免疫机制而持续存在，直到抗生素干预。耐抗生素的N.淋病、这种疾病在妇女中通常无症状的性质以及缺乏针对关键毒力决定因素的疫苗，说明迫切需要在人类自然疾病期间研究这种病原体，以指导治疗感染的新疗法。本文提出的研究旨在鉴定淋球菌“体内表达因子”（IVEFs），其长期目标是将其开发为新的治疗靶点。我们的研究集中在中国南京国家性病控制中心（NCSTD）的一组受试者中，因为该地区的疾病水平较高，并且报告了耐药性增加的淋球菌菌株。使用从南京队列获得的尿道和阴道灌洗样本，结合RNA深度测序，我们首次鉴定了自然感染期间表达的基因，这些基因在体外条件下培养的相应淋球菌菌株中未检测到。在男性和女性自然粘膜感染期间检测到高水平表达的常见淋球菌基因组中，有一组以前未表征的淋球菌噬菌体和假设基因以及编码抗菌药物耐药决定簇的基因。我们假设淋球菌在体内表达的基因以前没有在体外被发现。尽管女性和男性受试者在自然感染期间表达的淋球菌转录组存在差异，但可以鉴定出共同的基因，并有可能成为新的治疗靶点。我们提出以下目标来解决这个假设：目标1。定义N.在男性和女性生殖道的体内感染期间表达的淋病转录组，并鉴定淋球菌IVEFs。目标2.明确IVEF各亚型在N.淋病发病机制本申请中提出的研究是第一次检查N.淋病在自然粘膜感染过程中，并确定和表征新的基因表达的体内尚未假设存在。