The ClpXP protease contributes to Staphylococcus aureus pneumonia and activates a reduced host response. C57BL/6J mice were intranasally infected with 4 × 107 colony-forming units of wild-type (WT) S. aureus USA300 and other strains for 24 hours. A, Bacterial counts from bronchoalveolar lavage fluid (BALF) and lung homogenate. B, Protein content in BALF. C and D, Flow cytometry analysis on cells from BALF. C, Neutrophil counts from the airway. D, Additional cell counts in the airway. E, BALF was quantified for cytokine expression using enzyme-linked immunosorbent assay. F, Cytokine gene expression 2 hours after bone marrow–derived dendritic cell stimulation. n = 2 for uninfected, 11 for WT, 12 for ∆clpP and ∆clpX, and 7 for complemented strains. Each point represents a mouse. Graphs display mean with standard deviation. Data were assessed using nonparametric analysis of variance with Kruskal–Wallis test. *P < .05, **P < .01, and ***P < .001, compared to WT. Abbreviations: AM, alveolar macrophages; BALF, bronchoalveolar lavage fluid; CFU, colony-forming units; DC, dendritic cells; IL, interleukin; IM, interstitial macrophages; KC, keratinocyte chemoattractant; NK, natural killer; TNF, tumor necrosis factor; UN, uninfected; WT, wild-type.