Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage

ABSTRACT Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Neisseria meningiti...

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Autores principales:	Luke R. Green, Ali A. Al-Rubaiawi, Mohammad A. R. M. Al-Maeni, Odile B. Harrison, Matthew Blades, Neil J. Oldfield, David P. J. Turner, Martin C. J. Maiden, Christopher D. Bayliss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Neisseria meningitidis horizontal gene transfer localized hypermutation meningitis meningococcus phase variation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/742797ecf880443b9021ddd535f6ff03
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spelling	oai:doaj.org-article:742797ecf880443b9021ddd535f6ff032021-11-15T15:57:02ZLocalized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage10.1128/mBio.03068-192150-7511https://doaj.org/article/742797ecf880443b9021ddd535f6ff032020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03068-19https://doaj.org/toc/2150-7511ABSTRACT Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Neisseria meningitidis. Interrogation of whole-genome sequences for paired isolates from 25 carriers showed that de novo mutations were infrequent, while horizontal gene transfer occurred in 16% of carriers. Examination of multiple isolates per time point enabled separation of sporadic and transient allelic variation from directional variation. A comprehensive comparative analysis of directional allelic variation with hypermutation of simple sequence repeats and hyperrecombination of class 1 type IV pilus genes detected an average of seven events per carrier and 2:1 bias for changes due to localized hypermutation. Directional genetic variation was focused on the outer membrane with 69% of events occurring in genes encoding enzymatic modifiers of surface structures or outer membrane proteins. Multiple carriers exhibited directional and opposed switching of allelic variants of the surface-located Opa proteins that enables continuous expression of these adhesins alongside antigenic variation. A trend for switching from PilC1 to PilC2 expression was detected, indicating selection for specific alterations in the activities of the type IV pilus, whereas phase variation of restriction modification (RM) systems, as well as associated phasevarions, was infrequent. We conclude that asymptomatic meningococcal carriage on mucosal surfaces is facilitated by frequent localized hypermutation and horizontal gene transfer affecting genes encoding surface modifiers such that optimization of adhesive functions occurs alongside escape of immune responses by antigenic variation. IMPORTANCE Many bacterial pathogens coexist with host organisms, rarely causing disease while adapting to host responses. Neisseria meningitidis, a major cause of meningitis and septicemia, is a frequent persistent colonizer of asymptomatic teenagers/young adults. To assess how genetic variation contributes to host persistence, whole-genome sequencing and hypermutable sequence analyses were performed on multiple isolates obtained from students naturally colonized with meningococci. High frequencies of gene transfer were observed, occurring in 16% of carriers and affecting 51% of all nonhypermutable variable genes. Comparative analyses showed that hypermutable sequences were the major mechanism of variation, causing 2-fold more changes in gene function than other mechanisms. Genetic variation was focused on genes affecting the outer membrane, with directional changes in proteins responsible for bacterial adhesion to host surfaces. This comprehensive examination of genetic plasticity in individual hosts provides a significant new platform for rationale design of approaches to prevent the spread of this pathogen.Luke R. GreenAli A. Al-RubaiawiMohammad A. R. M. Al-MaeniOdile B. HarrisonMatthew BladesNeil J. OldfieldDavid P. J. TurnerMartin C. J. MaidenChristopher D. BaylissAmerican Society for MicrobiologyarticleNeisseria meningitidishorizontal gene transferlocalized hypermutationmeningitismeningococcusphase variationMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neisseria meningitidis horizontal gene transfer localized hypermutation meningitis meningococcus phase variation Microbiology QR1-502
spellingShingle	Neisseria meningitidis horizontal gene transfer localized hypermutation meningitis meningococcus phase variation Microbiology QR1-502 Luke R. Green Ali A. Al-Rubaiawi Mohammad A. R. M. Al-Maeni Odile B. Harrison Matthew Blades Neil J. Oldfield David P. J. Turner Martin C. J. Maiden Christopher D. Bayliss Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
description	ABSTRACT Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Neisseria meningitidis. Interrogation of whole-genome sequences for paired isolates from 25 carriers showed that de novo mutations were infrequent, while horizontal gene transfer occurred in 16% of carriers. Examination of multiple isolates per time point enabled separation of sporadic and transient allelic variation from directional variation. A comprehensive comparative analysis of directional allelic variation with hypermutation of simple sequence repeats and hyperrecombination of class 1 type IV pilus genes detected an average of seven events per carrier and 2:1 bias for changes due to localized hypermutation. Directional genetic variation was focused on the outer membrane with 69% of events occurring in genes encoding enzymatic modifiers of surface structures or outer membrane proteins. Multiple carriers exhibited directional and opposed switching of allelic variants of the surface-located Opa proteins that enables continuous expression of these adhesins alongside antigenic variation. A trend for switching from PilC1 to PilC2 expression was detected, indicating selection for specific alterations in the activities of the type IV pilus, whereas phase variation of restriction modification (RM) systems, as well as associated phasevarions, was infrequent. We conclude that asymptomatic meningococcal carriage on mucosal surfaces is facilitated by frequent localized hypermutation and horizontal gene transfer affecting genes encoding surface modifiers such that optimization of adhesive functions occurs alongside escape of immune responses by antigenic variation. IMPORTANCE Many bacterial pathogens coexist with host organisms, rarely causing disease while adapting to host responses. Neisseria meningitidis, a major cause of meningitis and septicemia, is a frequent persistent colonizer of asymptomatic teenagers/young adults. To assess how genetic variation contributes to host persistence, whole-genome sequencing and hypermutable sequence analyses were performed on multiple isolates obtained from students naturally colonized with meningococci. High frequencies of gene transfer were observed, occurring in 16% of carriers and affecting 51% of all nonhypermutable variable genes. Comparative analyses showed that hypermutable sequences were the major mechanism of variation, causing 2-fold more changes in gene function than other mechanisms. Genetic variation was focused on genes affecting the outer membrane, with directional changes in proteins responsible for bacterial adhesion to host surfaces. This comprehensive examination of genetic plasticity in individual hosts provides a significant new platform for rationale design of approaches to prevent the spread of this pathogen.
format	article
author	Luke R. Green Ali A. Al-Rubaiawi Mohammad A. R. M. Al-Maeni Odile B. Harrison Matthew Blades Neil J. Oldfield David P. J. Turner Martin C. J. Maiden Christopher D. Bayliss
author_facet	Luke R. Green Ali A. Al-Rubaiawi Mohammad A. R. M. Al-Maeni Odile B. Harrison Matthew Blades Neil J. Oldfield David P. J. Turner Martin C. J. Maiden Christopher D. Bayliss
author_sort	Luke R. Green
title	Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
title_short	Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
title_full	Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
title_fullStr	Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
title_full_unstemmed	Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage
title_sort	localized hypermutation is the major driver of meningococcal genetic variability during persistent asymptomatic carriage
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/742797ecf880443b9021ddd535f6ff03
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Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage

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