Host Chemokines Bind to Staphylococcus aureus and Stimulate Protein A Release*

There are few examples of host signals that are beneficial to bacteria during infection. Here we found that 31 out of 42 host immunoregulatory chemokines were able to induce release of the virulence factor protein A (SPA) from a strain of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Detailed study of chemokine CXCL9 revealed that SPA release occurred through a post-translational mechanism and was inversely proportional to bacterial density. CXCL9 bound specifically to the cell membrane of CA-MRSA, and the related SPA-releasing chemokine CXCL10 bound to both cell wall and cell membrane. Clinical samples from patients infected with S. aureus and samples from a mouse model of CA-MRSA skin abscess all contained extracellular SPA. Further, SPA-releasing chemokines were present in mouse skin lesions infected with CA-MRSA. Our data identify a potential new mode of immune evasion, in which the pathogen exploits a host defense factor to release a virulence factor; moreover, chemokine binding may serve a scavenging function in immune evasion by S. aureus.

[1]  D. Missiakas,et al.  Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice , 2010, The Journal of experimental medicine.

[2]  I. Woolley,et al.  Shedding light on DARC: the role of the Duffy antigen/receptor for chemokines in inflammation, infection and malignancy , 2009, Inflammation Research.

[3]  R. Daum,et al.  Transcription of Inflammatory Genes in the Lung after Infection with Community-Associated Methicillin-Resistant Staphylococcus aureus: a Role for Panton-Valentine Leukocidin? , 2009, Infection and Immunity.

[4]  I. McInnes,et al.  Atypical chemokine receptors in inflammatory disease. , 2009, Current molecular medicine.

[5]  E. Calvo,et al.  Protein A-Mediated Multicellular Behavior in Staphylococcus aureus , 2008, Journal of bacteriology.

[6]  L. Finelli,et al.  Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection - United States, April-August 2009. , 2009 .

[7]  C. Whitney,et al.  Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May-August 2009. , 2009, MMWR. Morbidity and mortality weekly report.

[8]  D. Kasper,et al.  IFN-γ Regulated Chemokine Production Determines the Outcome of Staphylococcus aureus Infection1 , 2008, The Journal of Immunology.

[9]  P. Murphy,et al.  Chemokine Receptor CX3CR1 Mediates Skin Wound Healing by Promoting Macrophage and Fibroblast Accumulation and Function1 , 2008, The Journal of Immunology.

[10]  J. Banchereau,et al.  Pyogenic Bacterial Infections in Humans with MyD88 Deficiency , 2003, Science.

[11]  Roberta B Carey,et al.  Invasive methicillin-resistant Staphylococcus aureus infections in the United States. , 2007, JAMA.

[12]  Gerhard Klebe,et al.  PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations , 2007, Nucleic Acids Res..

[13]  D. Boyle,et al.  Cutting Edge: Bim Is Required for Superantigen-Mediated B Cell Death1 , 2007, The Journal of Immunology.

[14]  E. Delong,et al.  Staphylococcus aureus Panton-Valentine Leukocidin Causes Necrotizing Pneumonia , 2007, Science.

[15]  A. Rot,et al.  Throwing light on DARC. , 2006, Biochemical Society transactions.

[16]  O. Schneewind,et al.  Surface Proteins and Exotoxins Are Required for the Pathogenesis of Staphylococcus aureus Pneumonia , 2006, Infection and Immunity.

[17]  David E. Swayne,et al.  Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus , 2006, Nature.

[18]  A. Tzianabos,et al.  CD4+ T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections , 2006, Proceedings of the National Academy of Sciences.

[19]  G. Sensabaugh,et al.  Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus , 2006, The Lancet.

[20]  O. Zaborina,et al.  Recognition of Host Immune Activation by Pseudomonas aeruginosa , 2005, Science.

[21]  M. Gilmore,et al.  Enterococcus faecalis Senses Target Cells and in Response Expresses Cytolysin , 2004, Science.

[22]  G. Silverman,et al.  Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Bharat Reddy,et al.  Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1 , 2004, Nature Medicine.

[24]  Nathan A. Baker,et al.  PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations , 2004, Nucleic Acids Res..

[25]  D. Hoover,et al.  Many chemokines including CCL20/MIP‐3α display antimicrobial activity , 2003 .

[26]  Niklas Palmqvist,et al.  Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. , 2002, Microbial pathogenesis.

[27]  M. Otto.  Staphylococcus aureus and Staphylococcus epidermidis peptide pheromones produced by the accessory gene regulator agr system , 2001, Peptides.

[28]  M. Burdick,et al.  Cutting Edge: IFN-Inducible ELR− CXC Chemokines Display Defensin-Like Antimicrobial Activity1 , 2001, The Journal of Immunology.

[29]  W. Hickey,et al.  CXC Chemokine Receptor-2 Ligands Are Required for Neutrophil-Mediated Host Defense in Experimental Brain Abscesses1 , 2001, The Journal of Immunology.

[30]  S. Akira,et al.  Cutting Edge: TLR2-Deficient and MyD88-Deficient Mice Are Highly Susceptible to Staphylococcus aureus Infection1 , 2000, The Journal of Immunology.

[31]  A. Tarkowski,et al.  Role of Neutrophil Leukocytes in Cutaneous Infection Caused by Staphylococcus aureus , 2000, Infection and Immunity.

[32]  J J Sixma,et al.  Protein A is the von Willebrand factor binding protein on Staphylococcus aureus. , 2000, Blood.

[33]  S. Sasaki,et al.  Interleukin-4 and Interleukin-10 Are Involved in Host Resistance to Staphylococcus aureus Infection through Regulation of Gamma Interferon , 2000, Infection and Immunity.

[34]  S. Mazmanian,et al.  Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  S. Mazmanian,et al.  Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. , 1999, Science.

[36]  A. Tarkowski,et al.  Role of neutrophils in experimental septicemia and septic arthritis induced by Staphylococcus aureus , 1997, Infection and immunity.

[37]  R. Beavis,et al.  Bacterial interference caused by autoinducing peptide variants. , 1997, Science.

[38]  R. Beavis,et al.  Cell density control of staphylococcal virulence mediated by an octapeptide pheromone. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Rabin,et al.  Human Mig chemokine: biochemical and functional characterization , 1995, The Journal of experimental medicine.

[40]  A. Nakane,et al.  Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice , 1995, Infection and immunity.

[41]  P. Model,et al.  Cell wall sorting signals in surface proteins of gram‐positive bacteria. , 1993, The EMBO journal.

[42]  J. Musser,et al.  Murine model of cutaneous infection with gram-positive cocci , 1992, Infection and immunity.

[43]  V. Thomas,et al.  Characterization of clinical strains of Staphylococcus aureus associated with pneumonia , 1986, Journal of clinical microbiology.

[44]  H. Verbrugh,et al.  Protein A effect on alternative pathway complement activation and opsonization of Staphylococcus aureus , 1981, Infection and immunity.

[45]  H. Verbrugh,et al.  The role of Staphylococcus aureus cell-wall peptidoglycan, teichoic acid and protein A in the processes of complement activation and opsonization. , 1979, Immunology.

[46]  John E. Bennett,et al.  Principles and practice of infectious diseases. Vols 1 and 2. , 1979 .

[47]  R. Lindmark,et al.  Extracellular protein A from a methicillin-resistant strain of Staphylococcus aureus. , 1977, European journal of biochemistry.

[48]  J. Movitz.  Formation of extracellular protein A by Staphylococcus aureus. , 1976, European journal of biochemistry.

[49]  A. Forsgren.  Significance of Protein A Production by Staphylococci , 1970, Infection and immunity.

[50]  A. Grov.  Studies on antigen preparations from Staphylococcus aureus. 4. Separation and purification of protein A and a related precipitinogen. , 2009, Acta pathologica et microbiologica Scandinavica.

[51]  J. Wigglesworth.  EXPERIMENTAL GROWTH RETARDATION IN THE FOETAL RAT. , 1964, The Journal of pathology and bacteriology.

[52]  E. F. Gale,et al.  The assimilation of amino-acids by bacteria. XV. Actions of antibiotics on nucleic acid and protein synthesis in Staphylococcus aureus. , 1953, The Biochemical journal.