Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes

ABSTRACT Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the mil...

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Autores principales:	Grace Soong, Franklin Paulino, Sarah Wachtel, Dane Parker, Matthew Wickersham, Dongni Zhang, Armand Brown, Christine Lauren, Margaret Dowd, Emily West, Basil Horst, Paul Planet, Alice Prince
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a4d1954899034b38937686727a8fa46e
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spelling	oai:doaj.org-article:a4d1954899034b38937686727a8fa46e2021-11-15T15:41:33ZMethicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes10.1128/mBio.00289-152150-7511https://doaj.org/article/a4d1954899034b38937686727a8fa46e2015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00289-15https://doaj.org/toc/2150-7511ABSTRACT Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms. IMPORTANCE Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.Grace SoongFranklin PaulinoSarah WachtelDane ParkerMatthew WickershamDongni ZhangArmand BrownChristine LaurenMargaret DowdEmily WestBasil HorstPaul PlanetAlice PrinceAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Grace Soong Franklin Paulino Sarah Wachtel Dane Parker Matthew Wickersham Dongni Zhang Armand Brown Christine Lauren Margaret Dowd Emily West Basil Horst Paul Planet Alice Prince Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
description	ABSTRACT Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms. IMPORTANCE Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.
format	article
author	Grace Soong Franklin Paulino Sarah Wachtel Dane Parker Matthew Wickersham Dongni Zhang Armand Brown Christine Lauren Margaret Dowd Emily West Basil Horst Paul Planet Alice Prince
author_facet	Grace Soong Franklin Paulino Sarah Wachtel Dane Parker Matthew Wickersham Dongni Zhang Armand Brown Christine Lauren Margaret Dowd Emily West Basil Horst Paul Planet Alice Prince
author_sort	Grace Soong
title	Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
title_short	Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
title_full	Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
title_fullStr	Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
title_full_unstemmed	Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes
title_sort	methicillin-resistant <named-content content-type="genus-species">staphylococcus aureus</named-content> adaptation to human keratinocytes
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/a4d1954899034b38937686727a8fa46e
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Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> Adaptation to Human Keratinocytes

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