Sana S Dastgheyb, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Department of Orthopedic Surgery, Thomas Jefferson UniversityFollow
Amer E Villaruz, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Katherine Y Le, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Vee Y Tan, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Anthony C Duong, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Som S Chatterjee, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health; San Francisco General Hospital, University of California San Francisco
Gordon Y C Cheung, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Hwang-Soo Joo, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Noreen J Hickok, Department of Orthopedic Surgery, Thomas Jefferson University
Michael Otto, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Document Type

Article

Publication Date

7-1-2015

Comments

This article has been peer reviewed. It was published in: Infection and Immunity.

Volume 83, Issue 7, 2015, Pages 2966-2975.

The published version is available at DOI: 10.1128/IAI.00394-15

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Abstract

Staphylococcus aureus is a leading cause of prosthetic joint infections, which, as we recently showed, proceed with the involvement of biofilm-like clusters that cause recalcitrance to antibiotic treatment. Here we analyzed why these clusters grow extraordinarily large, reaching macroscopically visible extensions (>1 mm). We found that while specific S. aureus surface proteins are a prerequisite for agglomeration in synovial fluid, low activity of the Agr regulatory system and subsequent low production of the phenol-soluble modulin (PSM) surfactant peptides cause agglomerates to grow to exceptional dimensions. Our results indicate that PSMs function by disrupting interactions of biofilm matrix molecules, such as the polysaccharide intercellular adhesin (PIA), with the bacterial cell surface. Together, our findings support a two-step model of staphylococcal prosthetic joint infection: As we previously reported, interaction of S. aureus surface proteins with host matrix proteins such as fibrin initiates agglomeration; our present results show that, thereafter, the bacterial agglomerates grow to extremely large sizes owing to the lack of PSM expression under the specific conditions present in joints. Our findings provide a mechanistic explanation for the reported extreme resistance of joint infection to antibiotic treatment, lend support to the notions that Agr functionality and PSM production play a major role in defining different forms of S. aureus infection, and have important implications for antistaphylococcal therapeutic strategies.

PubMed ID

25964472

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