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Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia
  1. Ahmed Achouiti1,2,
  2. Thomas Vogl3,
  3. Henrik Endeman4,
  4. Brittany L Mortensen5,
  5. Pierre-Francois Laterre6,
  6. Xavier Wittebole6,
  7. Marieke A D van Zoelen7,
  8. Yaofang Zhang5,
  9. Jacobien J Hoogerwerf1,2,
  10. Sandrine Florquin8,
  11. Marcus J Schultz9,10,
  12. Jan C Grutters11,12,
  13. Douwe H Biesma13,
  14. Johannes Roth3,
  15. Eric P Skaar5,
  16. Cornelis van 't Veer1,2,
  17. Alex F de Vos1,2,
  18. Tom van der Poll1,2,14
  1. 1Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. 3Institute of Immunology, University of Muenster, Muenster, Germany
  4. 4Intensive Care Department, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
  5. 5Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  6. 6Department of Critical Care Medicine, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
  7. 7Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
  8. 8Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  9. 9Department of Intensive Care Medicine, University of Amsterdam, Amsterdam, The Netherlands
  10. 10Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  11. 11Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands
  12. 12Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
  13. 13Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands
  14. 14Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, The Netherlands
  1. Correspondence to Ahmed Achouiti, Academic Medical Center, Center for Experimental and Molecular Medicine, Meibergdreef 9, Room G2-130, Amsterdam 1105 AZ, The Netherlands; a.achouiti{at}amc.uva.nl

Abstract

Background Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia.

Methods MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro.

Results CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14.

Conclusions In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.

  • Bacterial Infection
  • Cytokine Biology
  • Innate Immunity
  • Neutrophil Biology
  • Respiratory Infection

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