In this study, we investigated the interactions of Staphylococcus aureus with mast cells, which are multifunctional sentinels lining the surfaces of the body. We found that bone marrow-derived murine mast cells (BMMC) exerted a powerful phagocytosis-independent antimicrobial activity against S. aureus. Both the release of extracellular traps as well as discharge of antimicrobial compounds were the mechanisms used by the BMMC to kill extracellular S. aureus. This was accompanied by the secretion of mediators such as TNF-α involved in the recruitment of effector cells. Interestingly, S. aureus subverted the extracellular antimicrobial activity of the BMMC by internalizing within these cells. S. aureus was also capable to internalize within human mast cells (HMC-1) and within murine skin mast cells during in vivo infection. Bacteria internalization was, at least in part, mediated by the α5β1 integrins expressed on the surface of the mast cell. In the intracellular milieu, the bacterium survived and persisted by increasing the cell wall thickness and by gaining access into the mast cell cytosol. The expression of α-hemolysin was essential for staphylococci intracellular persistence. By hiding within the long-life mast cells, staphylococci not only avoid clearance but also establish an infection reservoir that could contribute to chronic carriage.
© 2011 S. Karger AG, Basel
- Mast cells
- Staphylococcus aureus
- Antimicrobial activity
- Intracellular persistence
- Lowy FD: Staphylococcus aureus infections. N Engl J Med 1998;339:520–532.
- Gordon RJ, Lowy FD: Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2008;46(suppl 5):S350–S359.
- Kluytmans J, van Belkum A, Verbrugh H: Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997;10:505–520.
- Wertheim HF, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JA, van Keulen PH, Vandenbroucke-Grauls CM, Meester MH, Verbrugh HA: Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet 2004;364:703–705.
- Mekori YA, Metcalfe DD: Mast cells in innate immunity. Immunol Rev 2000;173:131–140.
- Kalesnikoff J, Galli SJ: New developments in mast cell biology. Nat Immunol 2008;9:1215–1223.
- Malaviya R, Abraham SN: Mast cell modulation of immune responses to bacteria. Immunol Rev 2001;179:16–24.
- Marshall JS: Mast cell responses to pathogens. Nat Rev Immunol 2004;4:787–799.
- Féger F, Varadaradjalou S, Gao Z, Abraham SN, Arock M: The role of mast cells in host defense and their subversion by bacterial pathogens. Trends Immunol 2002;23:151–157.
- Enoksson M, Ejendal KF, McAlpine S, Nilsson G, Lunderius-Andersson C: Human cord blood-derived mast cells are activated by the Nod1 agonist M-TriDAP to release pro-inflammatory cytokines and chemokines. J Innate Immun 2011;3:142–149.
- McLachlan JB, Abraham SN: Studies of the multifaceted mast cell response to bacteria. Curr Opin Microbiol 2001;4:260–266.
- Di Nardo A, Vitiello A, Gallo RL: Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol 2003;170:2274–2278.
- von Köckritz-Blickwede M, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, Medina E: Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008;111:3070–3080.
- Medina E: Neutrophil extracellular traps: a strategic tactic to defeat pathogens with potential consequences for the host. J Innate Immun 2009;1:176–180.
- Xiong YQ, Willard J, Yeaman MR, Cheung AL, Bayer AS: Regulation of Staphylococcus aureus α-toxin gene (hla) expression by agr, sarA, and sae in vitro and in experimental infective endocarditis. J Infect Dis 2006;194:1267–1275.
- Schmidt KA, Donegan NP, Kwan WA Jr, Cheung A: Influences of sigmaB and agr on expression of staphylococcal enterotoxin B (seb) in Staphylococcus aureus. Can J Microbiol 2004;50:351–360.
- Butterfield JH, Weiler D, Dewald G, Gleich GJ: Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res 1988;12:345–355.
- Spurr AR: A low-viscosity epoxy resin embedding medium for electron microscopy. J Ultrastruct Res 1969;26:31–43.
- Patalano F, Ruggieri F: Sodium cromoglycate: a review. Eur Respir J Suppl 1989;6:556s–560s.
- Rocha-de-Souza CM, Berent-Maoz B, Mankuta D, Moses AE, Levi-Schaffer F: Human mast cell activation by Staphylococcus aureus: interleukin-8 and tumor necrosis factor α release and the role of Toll-like receptor 2 and CD48 molecules. Infect Immun 2008;76:4489–4497.
- Sinha B, Fraunholz M: Staphylococcus aureus host cell invasion and post-invasion events. Int J Med Microbiol 2010;300:170–175.
- Jarry TM, Memmi G, Cheung AL: The expression of α-haemolysin is required for Staphylococcus aureus phagosomal escape after internalization in CFT-1 cells. Cell Microbiol 2008;10:1801–1814.
- Garzoni C, Kelley WL: Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol 2009;17:59–65.
- Kubica M, Guzik K, Koziel J, Zarebski M, Richter W, Gajkowska B, Golda A, Maciag-Gudowska A: A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages. PLoS One 2008;3:e1409.
- Voyich JM, Braughton KR, Sturdevant DE, Whitney AR, Saïd-Salim B, Porcella SF, Long RD, Dorward DW, Gardner DJ, Kreiswirth BN, Musser JM, DeLeo FR: Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. J Immunol 2005;175:3907–3919.
- Cossart P, Roy CR: Manipulation of host membrane machinery by bacterial pathogens. Curr Opin Cell Biol 2010;22:547–554.
- Shin JS, Gao Z, Abraham SN: Involvement of cellular caveolae in bacterial entry into mast cells. Science 2000;289:785–788.
- Bayles KW, Wesson CA, Liou LE, Fox LK, Bohach GA, Trumble WR: Intracellular Staphylococcus aureus escapes the endosome and induces apoptosis in epithelial cells. Infect Immun 1998;66:336–342.
- Bhakdi S, Tranum-Jensen J: A-Toxin of Staphylococcus aureus. Microbiol Rev 1991;55:733–751.
- Giese B, Dittmann S, Paprotka K, Levin K, Weltrowski A, Biehler D, Lâm TT, Sinha B, Fraunholz MJ: Staphylococcal α-toxin is not sufficient to mediate escape from phagolysosomes in upper-airway epithelial cells. Infect Immun 2009;77:3611–3625.
- Giese B, Glowinski F, Paprotka K, Dittmann S, Steiner T, Sinha B, Fraunholz MJ: Expression of δ-toxin by Staphylococcus aureus mediates escape from phago-endosomes of human epithelial and endothelial cells in the presence of β-toxin. Cell Microbiol 2011;13:316–329.
- Wilke GA, Bubeck Wardenburg J: Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin-mediated cellular injury. Proc Natl Acad Sci USA 2010;107:13473–13478.
- Kuroda M, Kuroda H, Oshima T, Takeuchi F, Mori H, Hiramatsu K: Two component system VraSR positively modulates the regulation of cell wall biosynthesis pathway in Staphylococcus aureus. Mol Microbiol 2003;49:807–821.
- Cui L, Neoh HM, Shoji M, Hiramatsu K: Contribution of vraSR and graSR point mutations to vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 2009;53:1231–1234.
- Garzoni C, Francois P, Huyghe A, Couzinet S, Tapparel C, Charbonnier Y, Renzoni A, Lucchini S, Lew DP, Vaudaux P, Kelley WL, Schrenzel J: A global view of Staphylococcus aureus whole genome expression upon internalization in human epithelial cells. BMC Genomics 2007;8:171.
- Schmidt F, Scharf SS, Hildebrandt P, Burian M, Bernhardt J, Dhople V, Kalinka J, Gutjahr M, Hammer E, Völker U: Time-resolved quantitative proteome profiling of host-pathogen interactions: the response of Staphylococcus aureus RN1HG to internalisation by human airway epithelial cells. Proteomics 2010;10:2801–2811.
- Cui L, Ma X, Sato K, Okuma K, Tenover FC, Mamizuka EM, Gemmell CG, Kim MN, Ploy MC, El-Solh N, Ferraz V, Hiramatsu K: Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J Clin Microbiol 2003;41:5–14.
- Guzik TJ, Bzowska M, Kasprowicz A, Czerniawska-Mysik G, Wójcik K, Szmyd D, Adamek-Guzik T, Pryjma J: Persistent skin colonization with Staphylococcus aureus in atopic dermatitis: relationship to clinical and immunological parameters. Clin Exp Allergy 2005;35:448–455.
- Liu FT, Goodarzi H, Chen HY: IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 2011, E-pub ahead of print.
- Benenson S, Zimhony O, Dahan D, Solomon M, Raveh D, Schlesinger Y, Yinnon AM: Atopic dermatitis – a risk factor for invasive Staphylococcus aureus infections: two cases and review. Am J Med 2005;118:1048–1051.
Dr. Eva Medina
Infection Immunology Research Group
Helmholtz Centre for Infection Research, Inhoffenstrasse 7
DE–38124 Braunschweig (Germany)
Tel. +49 531 6181 4500, E-Mail firstname.lastname@example.org
Received: February 8, 2011
Accepted after revision: March 22, 2011
Published online: June 8, 2011
Number of Print Pages : 13
Number of Figures : 8, Number of Tables : 0, Number of References : 40
Journal of Innate Immunity
Vol. 3, No. 5, Year 2011 (Cover Date: August 2011)
Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)
For additional information: http://www.karger.com/JIN
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.