Table_3_Genomic Insights on Variation Underlying Capsule Expression in Meningococcal Carriage Isolates From University Students, United States, 2015–2016.xlsx

In January and February 2015, Neisseria meningitidis serogroup B (NmB) outbreaks occurred at two universities in the United States, and mass vaccination campaigns using MenB vaccines were initiated as part of a public health response. Meningococcal carriage evaluations were conducted concurrently with vaccination campaigns at these two universities and at a third university, where no NmB outbreak occurred. Meningococcal isolates (N = 1,514) obtained from these evaluations were characterized for capsule biosynthesis by whole-genome sequencing (WGS). Functional capsule polysaccharide synthesis (cps) loci belonging to one of seven capsule genogroups (B, C, E, W, X, Y, and Z) were identified in 122 isolates (8.1%). Approximately half [732 (48.4%)] of isolates could not be genogrouped because of the lack of any serogroup-specific genes. The remaining 660 isolates (43.5%) contained serogroup-specific genes for genogroup B, C, E, W, X, Y, or Z, but had mutations in the cps loci. Identified mutations included frameshift or point mutations resulting in premature stop codons, missing or fragmented genes, or disruptions due to insertion elements. Despite these mutations, 49/660 isolates expressed capsule as observed with slide agglutination, whereas 45/122 isolates with functional cps loci did not express capsule. Neither the variable capsule expression nor the genetic variation in the cps locus was limited to a certain clonal complex, except for capsule null isolates (predominantly clonal complex 198). Most of the meningococcal carriage isolates collected from student populations at three US universities were non-groupable as a result of either being capsule null or containing mutations within the capsule locus. Several mutations inhibiting expression of the genes involved with the synthesis and transport of the capsule may be reversible, allowing the bacteria to switch between an encapsulated and non-encapsulated state. These findings are particularly important as carriage is an important component of the transmission cycle of the pathogen, and understanding the impact of genetic variations on the synthesis of capsule, a meningococcal vaccine target and an important virulence factor, may ultimately inform strategies for control and prevention of disease caused by this pathogen.

2015年1月至2月，美国两所高校暴发B群脑膜炎奈瑟菌（Neisseria meningitidis serogroup B，NmB）疫情，公共卫生应对部门随即启动B群脑膜炎球菌疫苗大规模接种工作。在此期间，研究团队于这两所暴发疫情的高校以及第三所未发生NmB疫情的高校中，同步开展脑膜炎球菌携带状况评估，并配合疫苗接种活动推进相关采样。本研究对此次评估获得的1514株脑膜炎球菌分离株，通过全基因组测序（WGS）对其荚膜生物合成特征进行解析。结果显示，122株分离株（占总样本的8.1%）中携带属于7个荚膜基因群（B、C、E、W、X、Y、Z）之一的功能性荚膜多糖合成（cps）基因座。约半数分离株[732株，占比48.4%]因缺乏任何血清群特异性基因，无法完成基因群分型。剩余660株分离株（占比43.5%）虽携带针对B、C、E、W、X、Y或Z基因群的血清群特异性基因，但cps基因座存在突变。已鉴定的突变类型包括：引发提前终止密码子的移码突变或点突变、基因缺失或片段化，以及插入元件介导的基因破坏。尽管存在上述突变，仍有49/660株分离株可通过玻片凝集试验检测到荚膜表达；而122株携带功能性cps基因座的分离株中，有45株未表达荚膜。除荚膜缺失型分离株（主要属于克隆复合体198）外，荚膜表达的变异性及cps基因座的遗传变异并未局限于某一特定克隆复合体。从美国三所高校学生群体中采集的脑膜炎球菌携带分离株，多数无法完成血清群分型，其原因在于菌株要么为荚膜缺失型，要么荚膜基因座存在突变。若干可抑制荚膜合成与转运相关基因表达的突变具有可逆性，能够使细菌在荚膜表达状态与无荚膜状态之间相互切换。上述研究发现具有重要公共卫生意义：携带状况是该病原体传播循环的核心环节；阐明遗传变异对荚膜合成的影响——荚膜既是脑膜炎球菌疫苗的关键靶标，也是重要的毒力因子——可为该病原体所致疾病的防控策略制定提供科学依据。