Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time

Prolonged survival in the host-bacteria microenvironment drives the selection of alternative cell types in Staphylococcus aureus, permitting quasi-dormant sub-populations to develop. These facilitate antibiotic tolerance, long-term growth, and relapse of infection. Small Colony Variants (SCV) are an...

ver descrição completa

Detalhes bibliográficos
Autores: Lee J, Carda-Diéguez M, Žiemyte M, Vreugde S, Cooksley C, Crosby HA, Horswill AR, Mira A, Zilm PS, Kidd SP
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p13948
Acesso em linha:https://fisabio.portalinvestigacion.com/publicaciones/13948
Access Level:acceso abierto
Palavra-chave:Small Colony Variants
Staphylococcus aureus
persistence
id ES_2a2df4edee1f24bc1229443d0d7cfc1b
oai_identifier_str oai:fisabio.fundanetsuite.com:p13948
network_acronym_str ES
network_name_str España
repository_id_str
spelling Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over TimeLee JCarda-Diéguez MŽiemyte MVreugde SCooksley CCrosby HAHorswill ARMira AZilm PSKidd SPSmall Colony VariantsStaphylococcus aureuspersistenceProlonged survival in the host-bacteria microenvironment drives the selection of alternative cell types in Staphylococcus aureus, permitting quasi-dormant sub-populations to develop. These facilitate antibiotic tolerance, long-term growth, and relapse of infection. Small Colony Variants (SCV) are an important cell type associated with persistent infection but are difficult to study in vitro due to the instability of the phenotype and reversion to the normal cell type. We have previously reported that under conditions of growth in continuous culture over a prolonged culture time, SCVs dominated a heterogenous population of cell types and these SCVs harbored a mutation in the DNA binding domain of the gene for the transcription factor, mgrA. To investigate this specific cell type further, S. aureus WCH-SK2-Delta mgrA itself was assessed with continuous culture. Compared to the wild type, the mgrA mutant strain required fewer generations to select for SCVs. There was an increased rate of mutagenesis within the Delta mgrA strain compared to the wild type, which we postulate is the mechanism explaining the increased emergence of SCV selection. The mgrA derived SCVs had impeded metabolism, altered MIC to specific antibiotics and an increased biofilm formation compared to non-SCV strain. Whole genomic sequencing detected single nucleotide polymorphisms (SNP) in phosphoglucosamine mutase glmM and tyrosine recombinase xerC. In addition, several genomic rearrangements were detected which affected genes involved in important functions such as antibiotic and toxic metal resistance and pathogenicity. Thus, we propose a direct link between mgrA and the SCV phenotype. IMPORTANCE Within a bacterial population, a stochastically generated heterogeneity of phenotypes allows continual survival against current and future stressors. The generation of a sub-population of quasi-dormant Small Colony Variants (SCV) in Staphylococcus aureus is such a mechanism, allowing for persistent or relapse of infection despite initial intervention seemingly clearing the infection. The use of continuous culture under clinically relevant conditions has allowed us to introduce time to the growth system and selects SCV within the population. This study provides valuable insights into the generation of SCV which are not addressed in standard laboratory generated models and reveals new pathways for understanding persistent S. aureus infection which can potentially be targeted in future treatments of persistent S. aureus infection.American Society for Microbiology2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/13948JOURNAL OF BACTERIOLOGYISSN: 10985530ISSNe: 00219193reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p139482026-06-11T12:45:17Z
dc.title.none.fl_str_mv Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
title Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
spellingShingle Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
Lee J
Small Colony Variants
Staphylococcus aureus
persistence
title_short Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
title_full Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
title_fullStr Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
title_full_unstemmed Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
title_sort Functional mgrA Influences Genetic Changes within a Staphylococcus aureus Cell Population over Time
dc.creator.none.fl_str_mv Lee J
Carda-Diéguez M
Žiemyte M
Vreugde S
Cooksley C
Crosby HA
Horswill AR
Mira A
Zilm PS
Kidd SP
author Lee J
author_facet Lee J
Carda-Diéguez M
Žiemyte M
Vreugde S
Cooksley C
Crosby HA
Horswill AR
Mira A
Zilm PS
Kidd SP
author_role author
author2 Carda-Diéguez M
Žiemyte M
Vreugde S
Cooksley C
Crosby HA
Horswill AR
Mira A
Zilm PS
Kidd SP
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Small Colony Variants
Staphylococcus aureus
persistence
topic Small Colony Variants
Staphylococcus aureus
persistence
description Prolonged survival in the host-bacteria microenvironment drives the selection of alternative cell types in Staphylococcus aureus, permitting quasi-dormant sub-populations to develop. These facilitate antibiotic tolerance, long-term growth, and relapse of infection. Small Colony Variants (SCV) are an important cell type associated with persistent infection but are difficult to study in vitro due to the instability of the phenotype and reversion to the normal cell type. We have previously reported that under conditions of growth in continuous culture over a prolonged culture time, SCVs dominated a heterogenous population of cell types and these SCVs harbored a mutation in the DNA binding domain of the gene for the transcription factor, mgrA. To investigate this specific cell type further, S. aureus WCH-SK2-Delta mgrA itself was assessed with continuous culture. Compared to the wild type, the mgrA mutant strain required fewer generations to select for SCVs. There was an increased rate of mutagenesis within the Delta mgrA strain compared to the wild type, which we postulate is the mechanism explaining the increased emergence of SCV selection. The mgrA derived SCVs had impeded metabolism, altered MIC to specific antibiotics and an increased biofilm formation compared to non-SCV strain. Whole genomic sequencing detected single nucleotide polymorphisms (SNP) in phosphoglucosamine mutase glmM and tyrosine recombinase xerC. In addition, several genomic rearrangements were detected which affected genes involved in important functions such as antibiotic and toxic metal resistance and pathogenicity. Thus, we propose a direct link between mgrA and the SCV phenotype. IMPORTANCE Within a bacterial population, a stochastically generated heterogeneity of phenotypes allows continual survival against current and future stressors. The generation of a sub-population of quasi-dormant Small Colony Variants (SCV) in Staphylococcus aureus is such a mechanism, allowing for persistent or relapse of infection despite initial intervention seemingly clearing the infection. The use of continuous culture under clinically relevant conditions has allowed us to introduce time to the growth system and selects SCV within the population. This study provides valuable insights into the generation of SCV which are not addressed in standard laboratory generated models and reveals new pathways for understanding persistent S. aureus infection which can potentially be targeted in future treatments of persistent S. aureus infection.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/13948
url https://fisabio.portalinvestigacion.com/publicaciones/13948
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv JOURNAL OF BACTERIOLOGY
ISSN: 10985530
ISSNe: 00219193
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405053158162432
score 15,812429

Registos relacionados