<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages

ABSTRACT Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S...

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Autores principales:	Ronald S. Flannagan, Robert C. Kuiack, Martin J. McGavin, David E. Heinrichs
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	antimicrobial peptides host-pathogen intracellular bacteria macrophages phagocytosis phagolysosome Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c87e4a6159cd462381942a06870104e0
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spelling	oai:doaj.org-article:c87e4a6159cd462381942a06870104e02021-11-15T16:00:14Z<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages10.1128/mBio.01143-182150-7511https://doaj.org/article/c87e4a6159cd462381942a06870104e02018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01143-18https://doaj.org/toc/2150-7511ABSTRACT Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S. aureus requires the GraXRS regulatory system for growth within this niche, while the SaeRS and AgrAC two-component regulatory systems and the α-phenol soluble modulins are dispensable. Importantly, we find that it is exposure to acidic pH that is required for optimal growth of S. aureus inside fully acidified macrophage phagolysosomes. Exposure of S. aureus to acidic pH evokes GraS signaling, which in turn elicits an adaptive response that endows the bacteria with increased resistance to antimicrobial effectors, such as antimicrobial peptides, encountered inside macrophage phagolysosomes. Notably, pH-dependent induction of antimicrobial peptide resistance in S. aureus requires the GraS sensor kinase. GraS and MprF, a member of the GraS regulon, play an important role for bacterial survival in the acute stages of systemic infection, where in murine models of infection, S. aureus resides within liver-resident Kupffer cells. We conclude that GraXRS represents a vital regulatory system that functions to allow S. aureus to evade killing, prior to commencement of replication, within host antibacterial immune cells. IMPORTANCE S. aureus can infect any site of the body, including the microbicidal phagolysosome of the macrophage. The ability of S. aureus to infect diverse niches necessitates that the bacteria be highly adaptable. Here we show that S. aureus responds to phagolysosome acidification to evoke changes in gene expression that enable the bacteria to resist phagolysosomal killing and to promote replication. Toxin production is dispensable for this response; however, the bacteria require the sensor kinase GraS, which transduces signals in response to acidic pH. GraS is necessary for phagolysosomal replication and survival of S. aureus in the acute stage of systemic infection. Disruption of this S. aureus adaptation would render S. aureus susceptible to phagocyte restriction.Ronald S. FlannaganRobert C. KuiackMartin J. McGavinDavid E. HeinrichsAmerican Society for Microbiologyarticleantimicrobial peptideshost-pathogenintracellular bacteriamacrophagesphagocytosisphagolysosomeMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial peptides host-pathogen intracellular bacteria macrophages phagocytosis phagolysosome Microbiology QR1-502
spellingShingle	antimicrobial peptides host-pathogen intracellular bacteria macrophages phagocytosis phagolysosome Microbiology QR1-502 Ronald S. Flannagan Robert C. Kuiack Martin J. McGavin David E. Heinrichs <named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
description	ABSTRACT Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S. aureus requires the GraXRS regulatory system for growth within this niche, while the SaeRS and AgrAC two-component regulatory systems and the α-phenol soluble modulins are dispensable. Importantly, we find that it is exposure to acidic pH that is required for optimal growth of S. aureus inside fully acidified macrophage phagolysosomes. Exposure of S. aureus to acidic pH evokes GraS signaling, which in turn elicits an adaptive response that endows the bacteria with increased resistance to antimicrobial effectors, such as antimicrobial peptides, encountered inside macrophage phagolysosomes. Notably, pH-dependent induction of antimicrobial peptide resistance in S. aureus requires the GraS sensor kinase. GraS and MprF, a member of the GraS regulon, play an important role for bacterial survival in the acute stages of systemic infection, where in murine models of infection, S. aureus resides within liver-resident Kupffer cells. We conclude that GraXRS represents a vital regulatory system that functions to allow S. aureus to evade killing, prior to commencement of replication, within host antibacterial immune cells. IMPORTANCE S. aureus can infect any site of the body, including the microbicidal phagolysosome of the macrophage. The ability of S. aureus to infect diverse niches necessitates that the bacteria be highly adaptable. Here we show that S. aureus responds to phagolysosome acidification to evoke changes in gene expression that enable the bacteria to resist phagolysosomal killing and to promote replication. Toxin production is dispensable for this response; however, the bacteria require the sensor kinase GraS, which transduces signals in response to acidic pH. GraS is necessary for phagolysosomal replication and survival of S. aureus in the acute stage of systemic infection. Disruption of this S. aureus adaptation would render S. aureus susceptible to phagocyte restriction.
format	article
author	Ronald S. Flannagan Robert C. Kuiack Martin J. McGavin David E. Heinrichs
author_facet	Ronald S. Flannagan Robert C. Kuiack Martin J. McGavin David E. Heinrichs
author_sort	Ronald S. Flannagan
title	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
title_short	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
title_full	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
title_fullStr	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
title_full_unstemmed	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages
title_sort	<named-content content-type="genus-species">staphylococcus aureus</named-content> uses the graxrs regulatory system to sense and adapt to the acidified phagolysosome in macrophages
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c87e4a6159cd462381942a06870104e0
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<named-content content-type="genus-species">Staphylococcus aureus</named-content> Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages

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