title: Toll-like receptor 9 enhances bacterial clearance and limits lung consolidation in murine pneumonia caused by methicillin resistantStaphylococcus aureus.
abstract: Methicillin-resistantStaphylococcus aureus(MRSA) is an important pathogen in pneumonia, associated with severe lung damage. Tissue injury causes release of Damage Associated Molecular Patterns (DAMPs), which may perpetuate inflammation. DNA has been implicated as a DAMP that activates inflammation through Toll-like receptor (TLR)9. The aim of this study was to evaluate the role of TLR9 in MRSA pneumonia. Wild-type (Wt) and TLR9 knockout (tlr9-/-) mice were infected intranasally with MRSA USA300 (BK 11540) (5E7CFU) and euthanized at 6,24,48 or 72 hours for analyses. MRSA pneumonia was associated with profound release of cell-free host DNA in the airways, as reflected by increases in nucleosome and DNA levels in bronchoalveolar lavage fluid (BALF), accompanied by transient detection of pathogen DNA in MRSA-free BALF supernatants. In BALF, as compared to Wt -micetlr9-/-mice showed reduced TNFα and IL-6 levels at 6 hours and reduced bacterial clearance at 6 and 24 hours post infection. Furthermore,tlr9-/-mice exhibited a greater influx of neutrophils in BALF and increased lung consolidation at 24 and 48 hours. This study demonstrates the release of host- and pathogen-derived TLR9 ligands (DNA) into the alveolar space after infection with MRSA via the airways and suggests that TLR9 has pro-inflammatory effects during MRSA pneumonia associated with enhanced bacterial clearance and limitation of lung consolidation.
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Anne Jan
authors: AJ
authors: van der Meer
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Achmed
authors: A
authors: Achouiti
authors: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Arie
authors: A
authors: van der Ende
authors: Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands.
authors: Aicha A
authors: AA
authors: Soussan
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Sandrine
authors: S
authors: Florquin
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Alex
authors: A
authors: de Vos
authors: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands.
authors: Sacha S
authors: SS
authors: Zeerleder
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Tom
authors: T
authors: van der Poll
keywords: DNA; Interleukin-6; Neutrophils; Nucleosomes; Tumor Necrosis Factor-alpha