Acquisition of gonococcal denitrification apparatus in the Neisseria meningitidis urethritis clade

脑膜炎奈瑟菌尿道炎分支中淋菌反硝化装置的获得

• 批准号: 10317302
• 负责人: Jennifer L Edwards
• 金额: $ 20.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317302
• 关键词: Address; Aerobic; Affect; Anaerobic Bacteria; Area; Automobile Driving; Azithromycin; Bacteria; Bacterial Meningitis; Biological; Burkholderia; Cells; Cervix Uteri; Cities; Clinical; Communicable Diseases; Communities; Complex; Conjunctivitis; Data; Disease; Disease Outbreaks; Elements; Environment; Epidemiology; Event; Evolution; Female; Gene Conversion; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genitourinary system; Genome; Genotype; Geographic state; Growth; Hemophilus; Heterosexuals; Human; Hybrids; Immune response; Individual; Infection; Innate Immune Response; Intergenic Sequence; Kingella; Male urethral structure; Mediating; Meningitis; Meningococcal vaccine; Modeling; Molecular; Moraxella; Mucous Membrane; Mutate; Mutation; Nasopharynx; National Institute of Allergy and Infectious Disease; Neisseria gonorrhoeae; Neisseria meningitidis; Neonatal; Nitrates; Nitric Oxide; Nitrite Reductase; Nitrites; Nitrous Oxide; Nucleic Acid Regulatory Sequences; Ohio; Oxygen; Pathogenesis; Pathogenicity; Pathway interactions; Pharyngeal structure; Phenotype; Physiological; Play; Population; Predisposition; Prevalence; Publishing; Regulatory Element; Reporter; Reporting; Respiration; Sepsis; Sexual Transmission; Sexually Transmitted Diseases; Site; Site-Directed Mutagenesis; Survivors; System; Toxic effect; Transcript; Urethra; Urethritis; Urine; Vietnam; Work; capsule; denitrification; genetic signature; genome sequencing; human pathogen; in vivo; insight; male; men; mortality; nitric oxide reductase; novel; opportunistic pathogen; pathogen; pressure; promoter; rectal; reproductive; respiratory pathogen; trait; transcriptome; transcriptome sequencing; urogenital tract; whole genome

Project Summary Neisseria meningitidis is carried in the nasopharynx asymptomatically by up to 5-10% of the human population and remains a leading cause of meningitis and rapidly fatal sepsis, usually in otherwise healthy individuals. Historically, N. meningitidis has not been a significant sexually transmitted pathogen. However, since 2015 recent outbreaks of sexually transmitted meningococcal urethritis have occurred, primarily, in heterosexual males in over thirteen US states, the UK, and Vietnam. Unlike previous sporadic cases of meningococcal urethritis, these urethritis cases are all caused by a capsule-defective meningococcal clade belonging to the hyper-invasive cc11.2 lineage. This clade of N. meningitidis, like N. gonorrhoeae, causes male urethritis in unprecedented numbers in communities, can also be isolated from the pharynx and rectal tract, and can cause meningococcemia and meningitis, as well as other mucosal infections (neonatal conjunctivitis). Whereas isolated cases of urogenital colonization and urethritis caused by a range of meningococcal genotypes are reported, no other genotype has caused widespread urethritis outbreaks. These urethritis outbreaks suggest that this 11.2 lineage clade has acquired novel genetic and, thus, phenotypic changes that allow it to effectively colonize the urogenital tract, to adapt to local innate immune responses, and to cause urogenital tract disease. In support of this hypothesis, we discovered that all isolates of N. meningitidis urethritis clade, from multiple states and globally, but not sporadic meningococcal urethritis isolates, have the distinct N. gonorrhoeae denitrification apparatus - the gonococcal nitrite reductase, AniA, and the gonococcal nitric oxide (NO) reductase, NorB. This precise chromosomal gene conversion event has also endowed the clade with the gonococcal regulatory region that separates the divergent transcripts encoding aniA and norB. This aniA-norB conversion appears to provide a major adaptation to N. meningitidis for the oxygen-limited microaerobic/anaerobic urogenital environment and allowing emergence of this urethrotropic meningococcal clade. In two Specific Aims, we seek to define the unique regulatory and physiological traits conferred to this meningococcal clade through the gonococcal aniA-norB gene conversion event. In Aim 1, the unique hybrid transcriptional regulatory network, consisting of multiple meningococcal regulators controlling the divergently transcribed gonococcal aniA and norB promoters, will be examined in detail to define, new and critical, cis and trans regulatory elements in this clade. Global transcription profiles affected by the gene conversion in the clade will be examined using RNA-seq. In Aim 2, we will determine the impact of the gonococcal denitrification conversion on phenotypes important in urogenital pathogenesis: microaerobic growth, NO susceptibility and utilization, and defense against NO-mediated immune responses. Successful completion of these proposed studies will provide valuable insights into the continuing evolution of urethrotropic N. meningitidis and address two NIAID key priority areas, emerging infections and STIs.

项目摘要 脑膜炎奈瑟氏菌在鼻咽中无症状地由高达5-10%的人群携带 并且仍然是脑膜炎和迅速致命的败血症的主要原因，通常发生在其他方面健康的个体中。 历史上，N。脑膜炎并不是一种重要的性传播病原体。但从2015年开始 最近爆发的性传播脑膜炎球菌性尿道炎主要发生在异性恋者中， 美国13个州、英国和越南的男性。与以往的脑膜炎球菌性脑膜炎散发病例不同， 尿道炎，这些尿道炎病例都是由属于脑膜炎球菌分支的有包膜缺陷的脑膜炎球菌引起的。 高度侵袭性cc11.2谱系。这支N.脑膜炎，如N.淋病，导致男性尿道炎， 在社区中前所未有的数量，也可以从咽和直肠道分离，并可以引起 脑膜炎球菌血症和脑膜炎，以及其他粘膜感染（新生儿结膜炎）。虽然孤立 报告了由一系列脑膜炎球菌基因型引起的泌尿生殖道定植和尿道炎病例， 其他基因型引起了广泛的尿道炎爆发。这些尿道炎的爆发表明，这11.2 谱系进化枝获得了新的遗传，因此，表型变化，使其能够有效地殖民 泌尿生殖道，以适应局部先天性免疫反应，并引起泌尿生殖道疾病。支持 根据这一假设，我们发现所有的N.脑膜炎尿道炎分支，来自多个州， 在全球范围内，但不是散发性脑膜炎球菌性尿道炎分离株，具有不同的N.淋病反硝化作用 仪器-淋球菌亚硝酸盐还原酶，AniA，和淋球菌一氧化氮（NO）还原酶，NorB。这 精确的染色体基因转换事件也赋予进化枝淋球菌调节区 分离编码aniA和norB的不同转录本。这种aniA-norB转换似乎提供了 对N.用于氧限制性微需氧/厌氧泌尿生殖环境的脑膜炎， 从而导致这种嗜尿道脑膜炎球菌分支的出现。在两个具体目标中，我们寻求定义独特的 通过淋球菌aniA-norB基因赋予该脑膜炎球菌分支的调节和生理特性 转换事件。在目的1中，独特的杂交转录调控网络，由多个 脑膜炎球菌调节控制分歧转录淋球菌aniA和norB启动子，将是 详细检查，以确定新的和关键的，顺式和反式调节元件在这个分支。全局转录 将使用RNA-seq检查进化枝中受基因转换影响的谱。在目标2中，我们将确定 淋球菌脱氮转化对泌尿生殖道发病机制中重要表型的影响： 微需氧生长、NO易感性和利用以及对NO介导的免疫应答的防御。 成功完成这些拟议的研究将为持续演变提供宝贵的见解， 促尿道神经它涉及两个NIAID关键优先领域，即新出现的感染和性传播感染。