title: Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance.
abstract: BACKGROUND
  Staphylococcus aureus is the most common cause of healthcare-associated pneumonia. Despite the significant morbidity and mortality associated with the disease, animal models of S. aureus pneumonia are rare.
  
  
  METHODS
  We examined the pathogenicity of four different strains of S. aureus (both methicillin-sensitive and -resistant as well as Panton-Valentine leukocidin-positive and -negative) in four strains of immunocompetent inbred and outbred mice (FVB/N, C57Bl/6, BALB/c, ND4; n = 148). The immunological basis for the development of murine S. aureus pneumonia was then determined by selectively depleting neutrophils, lymphocytes, or pulmonary macrophages prior to the onset of infection. An additional cohort of animals was rendered immunosuppressed by induction of abdominal sepsis via cecal ligation and puncture 2, 4, or 7 d prior to the onset of pneumonia.
  
  
  RESULTS
  Nearly all immunocompetent mice survived, regardless of which strain of S. aureus was used or which strain of mouse was infected. Among animals with immune depletion or prior immunosuppression, survival was decreased only following neutrophil depletion (26% versus 90% alive at 7 d, P < 0.0001). Compared to immunocompetent animals, neutrophil-depleted mice with S. aureus pneumonia had delayed pulmonary bacterial clearance at 16 and 40 h but had no difference in levels of bacteremia. Neutrophil-depleted mice also had elevated levels of pulmonary monocyte chemotactic protein-1 (822 pg/mL versus 150 pg/mL, P < 0.05). In contrast, pulmonary histological appearance was similar in both groups as was dry/wet lung weight.
  
  
  CONCLUSIONS
  These results suggest that neutrophils play a critical role in the host response to S. aureus pneumonia, and the survival differences observed in neutrophil-depleted mice are associated with alterations in bacterial clearance and pulmonary cytokine response.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Robertson
authors.forename: Erin E
authors.initials: EE
authors.lastname: Perrone
authors.forename: Kevin W
authors.initials: KW
authors.lastname: McConnell
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Barrett
authors.initials: B
authors.lastname: Boody
authors.forename: Tejal
authors.initials: T
authors.lastname: Brahmbhatt
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Diacovo
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hogue
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000818:Animals; D008214:Lymphocytes / Q000502:physiology; D016676:Macrophages, Alveolar / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D011023:Pneumonia, Staphylococcal / Q000150:complications / Q000276:immunology*; D018805:Sepsis / Q000150:complications; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity