<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

ABSTRACT Staphylococcus aureus is a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting that S. aureus thwarts the development of sterilizing immunity. S. aureus strains that cause disease in humans produce up to five...

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Autores principales:	Evelien T. M. Berends, Xuhui Zheng, Erin E. Zwack, Mickaël M. Ménager, Michael Cammer, Bo Shopsin, Victor J. Torres
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	MRSA Staphylococcus aureus antigen-presenting cells dendritic cells immune system leukocidin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ea7cc10982854dd5b7ddef6e1533200d
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spelling	oai:doaj.org-article:ea7cc10982854dd5b7ddef6e1533200d2021-11-15T15:55:13Z<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin10.1128/mBio.01918-182150-7511https://doaj.org/article/ea7cc10982854dd5b7ddef6e1533200d2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01918-18https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting that S. aureus thwarts the development of sterilizing immunity. S. aureus strains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense against S. aureus infections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using an ex vivo infection model of primary human monocyte-derived dendritic cells, we found that S. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed that S. aureus targets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+ T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy of S. aureus whereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs. IMPORTANCE Antigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect of Staphylococcus aureus toxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability of S. aureus to blunt the function of DCs could help explain the high frequency of recurrent S. aureus infections. Taken together, the results from this study suggest that therapeutically targeting the S. aureus leukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.Evelien T. M. BerendsXuhui ZhengErin E. ZwackMickaël M. MénagerMichael CammerBo ShopsinVictor J. TorresAmerican Society for MicrobiologyarticleMRSAStaphylococcus aureusantigen-presenting cellsdendritic cellsimmune systemleukocidinMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	MRSA Staphylococcus aureus antigen-presenting cells dendritic cells immune system leukocidin Microbiology QR1-502
spellingShingle	MRSA Staphylococcus aureus antigen-presenting cells dendritic cells immune system leukocidin Microbiology QR1-502 Evelien T. M. Berends Xuhui Zheng Erin E. Zwack Mickaël M. Ménager Michael Cammer Bo Shopsin Victor J. Torres <italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
description	ABSTRACT Staphylococcus aureus is a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting that S. aureus thwarts the development of sterilizing immunity. S. aureus strains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense against S. aureus infections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using an ex vivo infection model of primary human monocyte-derived dendritic cells, we found that S. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed that S. aureus targets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+ T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy of S. aureus whereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs. IMPORTANCE Antigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect of Staphylococcus aureus toxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability of S. aureus to blunt the function of DCs could help explain the high frequency of recurrent S. aureus infections. Taken together, the results from this study suggest that therapeutically targeting the S. aureus leukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.
format	article
author	Evelien T. M. Berends Xuhui Zheng Erin E. Zwack Mickaël M. Ménager Michael Cammer Bo Shopsin Victor J. Torres
author_facet	Evelien T. M. Berends Xuhui Zheng Erin E. Zwack Mickaël M. Ménager Michael Cammer Bo Shopsin Victor J. Torres
author_sort	Evelien T. M. Berends
title	<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
title_short	<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
title_full	<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
title_fullStr	<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
title_full_unstemmed	<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin
title_sort	<italic toggle="yes">staphylococcus aureus</italic> impairs the function of and kills human dendritic cells via the lukab toxin
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ea7cc10982854dd5b7ddef6e1533200d
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<italic toggle="yes">Staphylococcus aureus</italic> Impairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

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