title: Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia.
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.
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Achouiti
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Intensive Care Department, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Henrik
authors.initials: H
authors.lastname: Endeman
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Mortensen
authors.affiliation: Department of Critical Care Medicine, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Pierre-Francois
authors.initials: PF
authors.lastname: Laterre
authors.affiliation: Department of Critical Care Medicine, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Wittebole
authors.affiliation: Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Yaofang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jacobien J
authors.initials: JJ
authors.lastname: Hoogerwerf
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Intensive Care Medicine, University of Amsterdam, Amsterdam, The Netherlands Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Grutters
authors.affiliation: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Douwe H
authors.initials: DH
authors.lastname: Biesma
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D040502:Calgranulin B / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*
chemical_list: D040502:Calgranulin B
keywords: Bacterial Infection; Cytokine Biology; Innate Immunity; Neutrophil Biology; Respiratory Infection