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: 10448441
• 负责人: Jennifer L Edwards
• 金额: $ 23.38万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448441
• 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; 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; transcription regulatory network; 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 奈瑟氏菌脑膜炎在鼻咽无症状中携带多达5-10％的人口 并且仍然是脑膜炎和迅速致命的败血症的主要原因，通常是在健康的个体中。 从历史上看，脑膜炎链球菌并不是一种重要的性传播病原体。但是，自2015年以来 最近发生的性传播脑膜炎球菌尿道炎的爆发主要是在异性恋中发生 在美国，英国和越南的13多个州的男性。与以前的脑膜炎球菌病例不同 尿道炎，这些尿道炎病例均由属于该囊肿的脑膜炎球菌对 侵入性CC11.2谱系。尼氏猪笼草的这种进化枝，如淋病链球菌，导致雄性尿道炎 社区中空前的数字也可以与咽部和直肠区隔离，并可能导致 脑膜炎球菌和脑膜炎以及其他粘膜感染（新生儿结膜炎）。而隔离 据报道，由一系列脑膜炎球菌基因型引起的泌尿生殖器定殖和尿道炎病例，无 其他基因型引起了广泛的尿道炎暴发。这些尿道炎暴发表明这11.2 谱系进化枝已经获得了新的遗传，因此，表型变化使其能够有效地定居 泌尿生殖道，适应局部先天免疫反应并引起泌尿生殖道疾病。支持 这个假设，我们发现脑膜炎脑炎的所有分离株，来自多个状态和 在全球范围但没有零星的脑膜炎球菌尿道炎分离株，具有独特的淋病脑硝基化。 设备 - 淋巴菌还原酶，ANA和淋球菌一氧化氮（NO）还原酶，NORB。这 精确的染色体基因转化事件也已与淋球菌调节区域赋予了进化枝 这将编码Ania和Norb的不同转录本分开。这种Ania-Norb转换似乎提供了 对氧气有限的微氧/厌氧环境和 允许出现这种尿道脑膜炎球菌。在两个具体的目标中，我们试图定义独特 通过淋球菌ania-norb基因赋予该脑膜炎球菌进化枝的调节和生理特征 转换事件。在AIM 1中，独特的混合转录调节网络，由多个组成 控制发散的淋球菌ANIA和NORB启动子的脑膜炎球菌调节器将是 详细检查以定义该进化枝中的新的和关键的，顺式和跨性别元素。全球转录 将使用RNA-seq检查受基因转化率影响的特征。在AIM 2中，我们将确定 淋球菌非硝化转化率对泌尿生殖发病机理重要的表型的影响： 微恐惧症的生长，无敏感性和利用以及对无介导的免疫反应的防御。 这些拟议的研究的成功完成将为持续发展提供宝贵的见解 尿道机脑膜炎脑膜炎，并针对两个NIAID关键优先级领域，即新兴的感染和性传播感染。

项目成果

Infection With the US Neisseria meningitidis Urethritis Clade Does Not Lower Future Risk of Urethral Gonorrhea.

感染美国脑膜炎奈瑟菌尿道炎分支不会降低未来尿道淋病的风险。

• DOI: 10.1093/cid/ciab824
• 发表时间: 2022
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Turner,AbigailNorris;Carter,AlexandriaM;Tzeng,Yih-Ling;Stephens,DavidS;Brown,MorganA;Snyder,BrandonM;Retchless,AdamC;Wang,Xin;Bazan,JoseA
• 通讯作者: Bazan,JoseA

Continuing genomic evolution of the Neisseria meningitidis cc11.2 urethritis clade, NmUC: a narrative review.

• DOI: 10.1099/mgen.0.001113
• 发表时间: 2023-10
• 期刊: Microbial genomics
• 影响因子: 3.9
• 作者: Rodriguez EI;Tzeng YL;Stephens DS
• 通讯作者: Stephens DS