Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection

Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survi...

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Main Authors:	Wilde, Aimee D., Snyder, Daniel J., Putnam, Nicole E., Valentino, Michael D., Hammer, Neal D., Lonergan, Zachery R., Hinger, Scott A., Aysanoa, Esar E., Blanchard, Catlyn, Dunman, Paul M., Wasserman, Gregory A., Chen, John, Shopsin, Bo, Gilmore, Michael S., Skaar, Eric P., Cassat, James E.
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684308/

id	pubmed-4684308
recordtype	oai_dc
spelling	pubmed-46843082015-12-31 Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection Wilde, Aimee D. Snyder, Daniel J. Putnam, Nicole E. Valentino, Michael D. Hammer, Neal D. Lonergan, Zachery R. Hinger, Scott A. Aysanoa, Esar E. Blanchard, Catlyn Dunman, Paul M. Wasserman, Gregory A. Chen, John Shopsin, Bo Gilmore, Michael S. Skaar, Eric P. Cassat, James E. Research Article Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction. Public Library of Science 2015-12-18 /pmc/articles/PMC4684308/ /pubmed/26684646 http://dx.doi.org/10.1371/journal.ppat.1005341 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Wilde, Aimee D. Snyder, Daniel J. Putnam, Nicole E. Valentino, Michael D. Hammer, Neal D. Lonergan, Zachery R. Hinger, Scott A. Aysanoa, Esar E. Blanchard, Catlyn Dunman, Paul M. Wasserman, Gregory A. Chen, John Shopsin, Bo Gilmore, Michael S. Skaar, Eric P. Cassat, James E.
spellingShingle	Wilde, Aimee D. Snyder, Daniel J. Putnam, Nicole E. Valentino, Michael D. Hammer, Neal D. Lonergan, Zachery R. Hinger, Scott A. Aysanoa, Esar E. Blanchard, Catlyn Dunman, Paul M. Wasserman, Gregory A. Chen, John Shopsin, Bo Gilmore, Michael S. Skaar, Eric P. Cassat, James E. Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
author_facet	Wilde, Aimee D. Snyder, Daniel J. Putnam, Nicole E. Valentino, Michael D. Hammer, Neal D. Lonergan, Zachery R. Hinger, Scott A. Aysanoa, Esar E. Blanchard, Catlyn Dunman, Paul M. Wasserman, Gregory A. Chen, John Shopsin, Bo Gilmore, Michael S. Skaar, Eric P. Cassat, James E.
author_sort	Wilde, Aimee D.
title	Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
title_short	Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
title_full	Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
title_fullStr	Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
title_full_unstemmed	Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection
title_sort	bacterial hypoxic responses revealed as critical determinants of the host-pathogen outcome by tnseq analysis of staphylococcus aureus invasive infection
description	Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684308/
_version_	1613514502630801408

Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection

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