<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

ABSTRACT Staphylococcus aureus is a major cause of prosthetic joint infection (PJI), which is characterized by biofilm formation. S. aureus biofilm skews the host immune response toward an anti-inflammatory profile by the increased recruitment of myeloid-derived suppressor cells (MDSCs) that attenua...

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Autores principales:	Megan E. Bosch, Blake P. Bertrand, Cortney E. Heim, Abdulelah A. Alqarzaee, Sujata S. Chaudhari, Amy L. Aldrich, Paul D. Fey, Vinai C. Thomas, Tammy Kielian
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	biofilm cytokines macrophages myeloid-derived suppressor cell Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a28ab5554534410984f1724ddc449c4f
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spelling	oai:doaj.org-article:a28ab5554534410984f1724ddc449c4f2021-11-15T16:19:07Z<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity10.1128/mBio.01581-202150-7511https://doaj.org/article/a28ab5554534410984f1724ddc449c4f2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01581-20https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is a major cause of prosthetic joint infection (PJI), which is characterized by biofilm formation. S. aureus biofilm skews the host immune response toward an anti-inflammatory profile by the increased recruitment of myeloid-derived suppressor cells (MDSCs) that attenuate macrophage proinflammatory activity, leading to chronic infection. A screen of the Nebraska Transposon Mutant Library identified several hits in the ATP synthase operon that elicited a heightened inflammatory response in macrophages and MDSCs, including atpA, which encodes the alpha subunit of ATP synthase. An atpA transposon mutant (ΔatpA) had altered growth kinetics under both planktonic and biofilm conditions, along with a diffuse biofilm architecture that was permissive for leukocyte infiltration, as observed by confocal laser scanning microscopy. Coculture of MDSCs and macrophages with ΔatpA biofilm elicited significant increases in the proinflammatory cytokines interleukin 12p70 (IL-12p70), tumor necrosis factor alpha (TNF-α), and IL-6. This was attributed to increased leukocyte survival resulting from less toxin and protease production by ΔatpA biofilm as determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The enhanced inflammatory response elicited by ΔatpA biofilm was cell lysis-dependent since it was negated by polyanethole sodium sulfanate treatment or deletion of the major autolysin, Atl. In a mouse model of PJI, ΔatpA-infected mice had decreased MDSCs concomitant with increased monocyte/macrophage infiltrates and proinflammatory cytokine production, which resulted in biofilm clearance. These studies identify S. aureus ATP synthase as an important factor in influencing the immune response during biofilm-associated infection and bacterial persistence. IMPORTANCE Medical device-associated biofilm infections are a therapeutic challenge based on their antibiotic tolerance and ability to evade immune-mediated clearance. The virulence determinants responsible for bacterial biofilm to induce a maladaptive immune response remain largely unknown. This study identified a critical role for S. aureus ATP synthase in influencing the host immune response to biofilm infection. An S. aureus ATP synthase alpha subunit mutant (ΔatpA) elicited heightened proinflammatory cytokine production by leukocytes in vitro and in vivo, which coincided with improved biofilm clearance in a mouse model of prosthetic joint infection. The ability of S. aureus ΔatpA to augment host proinflammatory responses was cell lysis-dependent, as inhibition of bacterial lysis by polyanethole sodium sulfanate or a ΔatpAΔatl biofilm did not elicit heightened cytokine production. These studies reveal a critical role for AtpA in shaping the host immune response to S. aureus biofilm.Megan E. BoschBlake P. BertrandCortney E. HeimAbdulelah A. AlqarzaeeSujata S. ChaudhariAmy L. AldrichPaul D. FeyVinai C. ThomasTammy KielianAmerican Society for Microbiologyarticlebiofilmcytokinesmacrophagesmyeloid-derived suppressor cellMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	biofilm cytokines macrophages myeloid-derived suppressor cell Microbiology QR1-502
spellingShingle	biofilm cytokines macrophages myeloid-derived suppressor cell Microbiology QR1-502 Megan E. Bosch Blake P. Bertrand Cortney E. Heim Abdulelah A. Alqarzaee Sujata S. Chaudhari Amy L. Aldrich Paul D. Fey Vinai C. Thomas Tammy Kielian <named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
description	ABSTRACT Staphylococcus aureus is a major cause of prosthetic joint infection (PJI), which is characterized by biofilm formation. S. aureus biofilm skews the host immune response toward an anti-inflammatory profile by the increased recruitment of myeloid-derived suppressor cells (MDSCs) that attenuate macrophage proinflammatory activity, leading to chronic infection. A screen of the Nebraska Transposon Mutant Library identified several hits in the ATP synthase operon that elicited a heightened inflammatory response in macrophages and MDSCs, including atpA, which encodes the alpha subunit of ATP synthase. An atpA transposon mutant (ΔatpA) had altered growth kinetics under both planktonic and biofilm conditions, along with a diffuse biofilm architecture that was permissive for leukocyte infiltration, as observed by confocal laser scanning microscopy. Coculture of MDSCs and macrophages with ΔatpA biofilm elicited significant increases in the proinflammatory cytokines interleukin 12p70 (IL-12p70), tumor necrosis factor alpha (TNF-α), and IL-6. This was attributed to increased leukocyte survival resulting from less toxin and protease production by ΔatpA biofilm as determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The enhanced inflammatory response elicited by ΔatpA biofilm was cell lysis-dependent since it was negated by polyanethole sodium sulfanate treatment or deletion of the major autolysin, Atl. In a mouse model of PJI, ΔatpA-infected mice had decreased MDSCs concomitant with increased monocyte/macrophage infiltrates and proinflammatory cytokine production, which resulted in biofilm clearance. These studies identify S. aureus ATP synthase as an important factor in influencing the immune response during biofilm-associated infection and bacterial persistence. IMPORTANCE Medical device-associated biofilm infections are a therapeutic challenge based on their antibiotic tolerance and ability to evade immune-mediated clearance. The virulence determinants responsible for bacterial biofilm to induce a maladaptive immune response remain largely unknown. This study identified a critical role for S. aureus ATP synthase in influencing the host immune response to biofilm infection. An S. aureus ATP synthase alpha subunit mutant (ΔatpA) elicited heightened proinflammatory cytokine production by leukocytes in vitro and in vivo, which coincided with improved biofilm clearance in a mouse model of prosthetic joint infection. The ability of S. aureus ΔatpA to augment host proinflammatory responses was cell lysis-dependent, as inhibition of bacterial lysis by polyanethole sodium sulfanate or a ΔatpAΔatl biofilm did not elicit heightened cytokine production. These studies reveal a critical role for AtpA in shaping the host immune response to S. aureus biofilm.
format	article
author	Megan E. Bosch Blake P. Bertrand Cortney E. Heim Abdulelah A. Alqarzaee Sujata S. Chaudhari Amy L. Aldrich Paul D. Fey Vinai C. Thomas Tammy Kielian
author_facet	Megan E. Bosch Blake P. Bertrand Cortney E. Heim Abdulelah A. Alqarzaee Sujata S. Chaudhari Amy L. Aldrich Paul D. Fey Vinai C. Thomas Tammy Kielian
author_sort	Megan E. Bosch
title	<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
title_short	<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
title_full	<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
title_fullStr	<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
title_full_unstemmed	<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity
title_sort	<named-content content-type="genus-species">staphylococcus aureus</named-content> atp synthase promotes biofilm persistence by influencing innate immunity
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/a28ab5554534410984f1724ddc449c4f
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<named-content content-type="genus-species">Staphylococcus aureus</named-content> ATP Synthase Promotes Biofilm Persistence by Influencing Innate Immunity

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