Genomic Insights on Variation Underlying Capsule Expression in Meningococcal Carriage Isolates From University Students, United States, 2015-2016.

Melissa Whaley ,Laurel T Jenkins,Fang Hu,Susanna Schmink,How-Yi Chang,Henju Marjuki,Sarah Mbaeyi,Anna M Acosta,Sandeep J Joseph,Adam C Retchless,Alexander Chen,Heidi M Soeters,Xin Wang,Nadav Topaz,Lorraine D Rodriguez‐Rivera ,Lucy A Mcnamara ,Evelene Steward‐Clark ,Jennifer D Thomas ,Jeni Vuong ,Marsenia H Mathis

doi:10.3389/fmicb.2022.815044

Abstract

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.

Highlights

Neisseria meningitidis (Nm, meningococcus) is a Gram-negative bacterium that colonizes the human upper respiratory tract
We characterized the capsule type and expression of Nm isolates obtained from carriage evaluations at three US universities in 2015–2016 and identified genetic variations within the cps loci of these isolates
While genogroup composition among Nm carriage isolates is similar to other carriage studies, E was the most common genogroup among genogroupable isolates, representing 26% of the collection

Summary

Introduction

Neisseria meningitidis (Nm, meningococcus) is a Gram-negative bacterium that colonizes the human upper respiratory tract. Meningococcal carriage may provide some protection from disease as colonization elicits a mucosal antibody response (Yazdankhah and Caugant, 2004). While mechanisms for the progression from meningococcal carriage to disease are still not well understood, meningococci can breach the mucosal barrier and invade the bloodstream to cause invasive disease such as bacteremia, septicemia, or meningitis, resulting in death in approximately 10–15% of cases (Tzeng and Stephens, 2000; Brandtzaeg and van Deuren, 2012). As the capsule is a major virulence factor, invasive disease is nearly always caused by meningococci expressing the capsule. Nm is divided into 12 serogroups based on structure of the capsular polysaccharide expressed. Serogroups A, B, C, W, X, and Y cause the majority of invasive disease (Tzeng et al, 2016). Rare cases of invasive disease caused by NmNG have been reported among patients who are immunocompromised, those with complement component deficiency (Ganesh et al, 2017; McNamara et al, 2019)

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