<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System

ABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfec...

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Autores principales:	Olivia A. Todd, Paul L. Fidel, Janette M. Harro, Jamese J. Hilliard, Christine Tkaczyk, Bret R. Sellman, Mairi C. Noverr, Brian M. Peters
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Candida albicans intraabdominal infection polymicrobial Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d0e5a7c9eab44807889d9025e2da07de
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id	oai:doaj.org-article:d0e5a7c9eab44807889d9025e2da07de
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans intraabdominal infection polymicrobial Microbiology QR1-502
spellingShingle	Candida albicans intraabdominal infection polymicrobial Microbiology QR1-502 Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
description	ABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with these pathogens results in synergistic lethality that is partially dependent on exacerbated prostaglandin signaling, while monomicrobial infection is nonlethal. Therefore, the objective of this study was to identify staphylococcal virulence determinants that drive lethal synergism during polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that coinfection with C. albicans led to a striking 80 to 100% mortality rate within 20 h postinoculation (p.i.) while monomicrobial infections were nonlethal. Use of a green fluorescent protein (GFP)-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by quantitative real-time PCR (qPCR), Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted alpha- and delta-toxins. C. albicans-mediated elevated toxin production and hemolytic activity were determined to be agrA dependent, and genetic knockout and complementation of hla identified alpha-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infections 8 h p.i. demonstrated equivalent bacterial burdens in the peritoneal cavity but significantly elevated levels of alpha-toxin (3-fold) and the eicosanoid prostaglandin E2 (PGE2) (4-fold) during coinfection. Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody. Collectively, these results define alpha-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human-pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo. IMPORTANCE Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so about how microbial “cross talk” shapes human health and disease. Candida albicans (a fungus) and Staphylococcus aureus (a bacterium) are formidable human nosocomial pathogens, causing severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. In this work, we have shown that coinfection with C. albicans and S. aureus is highly lethal, leading to >80% mortality by day 1 postinfection, whereas monoinfection with C. albicans or S. aureus does not cause mortality. This infectious synergism is dependent on the expression of staphylococcal alpha-toxin, and secretion of this potent virulence factor is actually augmented by C. albicans via an agr-dependent mechanism. Moreover, prophylactic neutralization of alpha-toxin with a monoclonal antibody is sufficient to elicit protection during coinfection. Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host.
format	article
author	Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters
author_facet	Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters
author_sort	Olivia A. Todd
title	<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
title_short	<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
title_full	<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
title_fullStr	<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
title_full_unstemmed	<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
title_sort	<named-content content-type="genus-species">candida albicans</named-content> augments <named-content content-type="genus-species">staphylococcus aureus</named-content> virulence by engaging the staphylococcal <italic toggle="yes">agr</italic> quorum sensing system
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d0e5a7c9eab44807889d9025e2da07de
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spelling	oai:doaj.org-article:d0e5a7c9eab44807889d9025e2da07de2021-11-15T15:55:25Z<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System10.1128/mBio.00910-192150-7511https://doaj.org/article/d0e5a7c9eab44807889d9025e2da07de2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00910-19https://doaj.org/toc/2150-7511ABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with these pathogens results in synergistic lethality that is partially dependent on exacerbated prostaglandin signaling, while monomicrobial infection is nonlethal. Therefore, the objective of this study was to identify staphylococcal virulence determinants that drive lethal synergism during polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that coinfection with C. albicans led to a striking 80 to 100% mortality rate within 20 h postinoculation (p.i.) while monomicrobial infections were nonlethal. Use of a green fluorescent protein (GFP)-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by quantitative real-time PCR (qPCR), Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted alpha- and delta-toxins. C. albicans-mediated elevated toxin production and hemolytic activity were determined to be agrA dependent, and genetic knockout and complementation of hla identified alpha-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infections 8 h p.i. demonstrated equivalent bacterial burdens in the peritoneal cavity but significantly elevated levels of alpha-toxin (3-fold) and the eicosanoid prostaglandin E2 (PGE2) (4-fold) during coinfection. Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody. Collectively, these results define alpha-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human-pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo. IMPORTANCE Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so about how microbial “cross talk” shapes human health and disease. Candida albicans (a fungus) and Staphylococcus aureus (a bacterium) are formidable human nosocomial pathogens, causing severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. In this work, we have shown that coinfection with C. albicans and S. aureus is highly lethal, leading to >80% mortality by day 1 postinfection, whereas monoinfection with C. albicans or S. aureus does not cause mortality. This infectious synergism is dependent on the expression of staphylococcal alpha-toxin, and secretion of this potent virulence factor is actually augmented by C. albicans via an agr-dependent mechanism. Moreover, prophylactic neutralization of alpha-toxin with a monoclonal antibody is sufficient to elicit protection during coinfection. Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host.Olivia A. ToddPaul L. FidelJanette M. HarroJamese J. HilliardChristine TkaczykBret R. SellmanMairi C. NoverrBrian M. PetersAmerican Society for MicrobiologyarticleCandida albicansintraabdominal infectionpolymicrobialMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)

<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System

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