Abstract
Methicillin-resistant Staphylococcus 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 -mice tlr9-/- 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.
Highlights
Infectious diseases remain a threat to public health in both developed countries and poor-resource settings
To examine whether methicillin- resistant S. aureus (MRSA) pneumonia is associated with the local release of cell-free host DNA, we measured nucleosomes in bronchoalveolar lavage fluid (BALF) obtained before and up to 72 h after infection (Figure 1A)
MRSA pneumonia was associated with elevated levels of MRSA DNA in BALF (Figure 1C); the highest levels were found early after infection (6 h), decreasing to undetectable levels at 48 h postinfection. These data show that MRSA pneumonia is associated with release of both pathogen- and hostderived DNA into BALF, whereby host DNA in particular appears late during infection, while pathogen DNA is found especially early after infection
Summary
Infectious diseases remain a threat to public health in both developed countries and poor-resource settings. The aging, infection-susceptible population combined with the rise of antibiotic resistant bacteria are important factors [1]. A striking example of a bacterial threat is S taphylococcus (S.) aureus [2]. This gram-positive pathogen is a leading cause of infection worldwide [3] and a major causative pathogen in nosocomial. Half of the world population carries S. aureus on their skin and in the United States alone more than 89 million people are colonized, of whom 2.3 million carry methicillin- resistant S. aureus (MRSA) [6,7]. Increasing our understanding of the pathophysiology of MRSA infections is a prerequisite for innovative treatments for this clinically highly relevant microorganism
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