Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance

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. MATERIALS AND 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 immunologic 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 days 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% vs. 90% alive at 7 days, p<0.0001). Compared to immunocompetent animals, neutrophil-depleted mice with S. aureus pneumonia had delayed pulmonary bacterial clearance at 16 and 40 hours but had no difference in levels of bacteremia. Neutrophil-depleted mice also had elevated levels of pulmonary MCP-1 (822 pg/ml vs. 150 pg/ml, p<0.05). In contrast, pulmonary histologic 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