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Cell Host Microbe. 2018 May 9;23(5):594-606.e7. doi: 10.1016/j.chom.2018.04.001.

Host Nitric Oxide Disrupts Microbial Cell-to-Cell Communication to Inhibit Staphylococcal Virulence.

Author information

1
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
2
Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
3
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
5
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
6
Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: fcfang@u.washington.edu.

Abstract

Staphylococcus aureus is a commensal bacterium that can asymptomatically colonize its host but also causes invasive infections. Quorum sensing regulates S. aureus virulence and the transition from a commensal to a pathogenic organism. However, little is known about how host innate immunity affects interbacterial communication. We show that nitric oxide suppresses staphylococcal virulence by targeting the Agr quorum sensing system. Nitric oxide-mediated inhibition occurs through direct modification of cysteine residues C55, C123, and C199 of the AgrA transcription factor. Cysteine modification decreases AgrA promoter occupancy as well as transcription of the agr operon and quorum sensing-activated toxin genes. In a staphylococcal pneumonia model, mice lacking inducible nitric oxide synthase develop more severe disease with heightened mortality and proinflammatory cytokine responses. In addition, staphylococcal α-toxin production increases in the absence of nitric oxide or nitric oxide-sensitive AgrA cysteine residues. Our findings demonstrate an anti-virulence mechanism for nitric oxide in innate immunity.

KEYWORDS:

S. aureus; bacterial pathogenesis; host defense; innate immunity; nitric oxide; quorum sensing; virulence

PMID:
29706505
PMCID:
PMC5949146
[Available on 2019-05-09]
DOI:
10.1016/j.chom.2018.04.001
[Indexed for MEDLINE]

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