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Identification of ligand specificity determinants in AgrC, the Staphylococcus aureus quorum-sensing receptor (Journal of Biological Chemistry (2012) 283, (8930-8938))
No full textIdentification of ligand specificity determinants in AgrC, the Staphylococcus aureus quorum-sensing receptor (Journal of Biological Chemistry (2012) 283, (8930-8938))(Erratum). Original article first published 2008 April 4.Additions and Corrections:
VOLUME 283 (2008) PAGES 8930 – 8938
DOI 10.1074/jbc.A112.710227
Identification of ligand specificity determinants in AgrC, the Staphylococcus aureus quorum-sensing receptor.
Edward Geisinger, Elizabeth A. George, John Chen, Tom W. Muir, and Richard P. Novick. John Chen should be included as an author of this work. The correct
author list is shown above. Dr. Chen’s affiliation is the Molecular Pathogenesis Program and Departments of Microbiology and Medicine, the Kimmel Center for Biology and Medicine of the Skirball Institute, New
York University School of Medicine, New York, New York 10016. Abstract for original 2008 article:
Activation of the agr system, a major regulator of staphylococcal virulence, is initiated by the binding of a specific autoinducing peptide (AIP) to the extracellular domain of AgrC, a classical receptor histidine protein kinase. There are four known agr specificity groups in Staphylococcus aureus, and we have previously localized the determinant of AIP receptor specificity to the C-terminal half of the AgrC sensor domain. We have now identified the specific amino acid residues that determine ligand activation specificity for agr groups I and IV, the two most closely related. Comparison of the AgrC-I and AgrC-IV sequences revealed a set of five divergent residues in the region of the second extracellular loop of the receptor that could be responsible. Accordingly, we exchanged these residues between AgrC-I and AgrC-IV and tested the resulting constructs for activation by the respective AIPs, measuring activation kinetics with a transcriptional fusion of blaZ to the principal agr promoter, P3. Exchange of all five residues caused a complete switch in receptor specificity. Replacement of two of the AgrC-IV residues by the corresponding residues in AgrC-I caused the receptor to be activated by AIP-I nearly as well as the wild type AgrC-I receptor. Replacement of two different AgrC-I residues by the corresponding AgrC-IV residues broadened receptor recognition specificity to include both AIPs. Various types of intermediate activity were observed with other replacement mutations. Preliminary characterization of the AgrC-I-AIP-I interaction suggests that ligand specificity may be sterically determined
<i>Plasmids: Biology and Impact in Biotechnology and Discovery</i>. Edited by Marcelo E. Tolmasky and Juan C. Alonso. Washington (DC): ASM Press. $150.00. xxi + 697 p.; ill.; index. ISBN: 978-1-55581-897-5. 2015.
No full textNovel insights into Staphylococcus aureus deep bone infections: the involvement of osteocytes
No full textPeriprosthetic joint infection (PJI) is a potentially devastating complication of orthopedic joint replacement surgery. PJI with associated osteomyelitis is particularly problematic and difficult to cure. Whether viable osteocytes, the predominant cell type in mineralized bone tissue, have a role in these infections is not clear, although their involvement might contribute to the difficulty in detecting and clearing PJI. Here, using Staphylococcus aureus, the most common pathogen in PJI, we demonstrate intracellular infection of human-osteocyte-like cells in vitro and S. aureus adaptation by forming quasi-dormant small-colony variants (SCVs). Consistent patterns of host gene expression were observed between in vitro-infected osteocyte-like cultures, an ex vivo human bone infection model, and bone samples obtained from PJI patients. Finally, we confirm S. aureus infection of osteocytes in clinical cases of PJI. Our findings are consistent with osteocyte infection being a feature of human PJI and suggest that this cell type may provide a reservoir for silent or persistent infection. We suggest that elucidating the molecular/cellular mechanism(s) of osteocyte-bacterium interactions will contribute to better understanding of PJI and osteomyelitis, improved pathogen detection, and treatment.IMPORTANCE Periprosthetic joint infections (PJIs) are increasing and are recognized as one of the most common modes of failure of joint replacements. Osteomyelitis arising from PJI is challenging to treat and difficult to cure and increases patient mortality 5-fold. Staphylococcus aureus is the most common pathogen causing PJI. PJI can have subtle symptoms and lie dormant or go undiagnosed for many years, suggesting persistent bacterial infection. Osteocytes, the major bone cell type, reside in bony caves and tunnels, the lacuno-canalicular system. We report here that S. aureus can infect and reside in human osteocytes without causing cell death both experimentally and in bone samples from patients with PJI. We demonstrate that osteocytes respond to infection by the differential regulation of a large number of genes. S. aureus adapts during intracellular infection of osteocytes by adopting the quasi-dormant small-colony variant (SCV) lifestyle, which might contribute to persistent or silent infection. Our findings shed new light on the etiology of PJI and osteomyelitis in general.Dongqing Yang, Asiri R. Wijenayaka, Lucian B. Solomon, Stephen M. Pederson, David M. Findlay, Stephen P. Kidd, Gerald J. Atkins, Mark S. Smeltzer, Richard P. Novic
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