The mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogen Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-β expression through a DAI/STING/TBK1/IRF3 cascade. Tlr4−/−, Myd88−/−, Trif−/−, and Nod2−/− mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN-α/β receptor null mice had significantly increased nasal colonization with S. pneumoniae compared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors.

The clinical manifestations of infection in cystic fibrosis (CF) are restricted to the lung, and involve a limited number of pathogens, suggesting a specific defect in mucosal immunity. We postulated that cystic fibrosis transmembrane conductance regulator (CTFR) mutations could affect the activation of type I interferon signaling in airway epithelial cells, which function in immune surveillance and initiate the recruitment and activation of immune cells. In response to infection with Pseudomonas aeruginosa, Ifnb was induced more than 100-fold in the murine lung, and the phosphorylation of STAT1 was similarly induced by the expected TLR4/TRIF/MD2/TBK1 cascade. The stimulation by P. aeruginosa of CF (IB3) cells and control (C-38) human cell lines similarly resulted in the induction of IFN-b, but to a significantly lower extent in CF airway cells. The potential consequences of diminished type I IFN signaling were demonstrated in a murine model of P. aeruginosa pneumonia, pretreatment with polyinosinic:polycytidylic acid significantly enhanced bacterial clearance and correlated with increased numbers of mature CD11c 1 / CD86 1 dendritic cells (DCs) in the lung. Using culture supernatants from CF or control cell lines stimulated with P. aeruginosa, we similarly demonstrated the diminished activation of human monocytederived DCs by incubation with CF compared with normal epithelial cell culture supernatants, which was dependent on IFN-b. These observations suggest that dysfunction of the CFTR in airway epithelial cells may contribute to impaired immune surveillance in the CF airway and resultant colonization by P. aeruginosa.

Staphylococcus aureus causes especially severe pulmonary infection, associated with high morbidity and mortality. In addition to the effects of specific virulence factors, it appears that the intensity of the host proinflammatory response, particularly in the initial stages of infection, contributes substantially to pulmonary damage. We tested the hypothesis that the CD11c ؉ leukocytes are important in the host response to pulmonary infection with methicillin-resistant S. aureus (MRSA) USA300. Clodronate-induced depletion of the alveolar macrophage population resulted in increased numbers of dendritic cells (DCs) and CD4؉ cells in bronchoalveolar lavage (BAL) fluid and was associated with significantly increased mortality by 18 h following S. aureus inoculation but had no effect on bacterial load or polymorphonuclear leukocyte (PMN) numbers in the lung. These clodronate-treated mice also had increased expression of interleukin-17A/F (IL-17A/F) and Staphylococcus aureus bacteria, particularly the epidemic methicillin-resistant USA300 strains, have recently been associated with severe invasive pneumonias in previously well individuals, as well as being a complication of influenza (15). These pneumonias are characterized by a predominant polymorphonuclear leukocyte (PMN) response with significant areas of necrosis and hemorrhage (6). Numerous studies have addressed which of the several virulence factors expressed by the USA300 strains are most important in the pathogenesis of pulmonary infection. In the C57BL/6J mouse model of acute pneumonia, the contributions of ␣-hemolysin (Hla) (3) and protein A (SpA) (8) have been well documented. The importance of Panton-Valentine leukocidin (PVL) has also been confirmed in a rabbit model of infection; rabbits, like humans, have highly PVL-susceptible leukocytes (6). Besides the direct toxicity of staphylococcal toxins, some of the pathological consequences of staphylococcal virulence factors are due to the intensity of the host immune response. Both Tnfr1 Ϫ/Ϫ (8) and Ifnar Ϫ/Ϫ (17) mice are highly resistant to S. aureus pneumonia and even to the USA300 strains expressing these virulence factors, suggesting that the intensity of the host immune response to infection is critical in the pathogenesis of severe pneumonia.Exactly which components of the innate immune response contribute to lethality in these models of acute S. aureus pneumonia has not been clearly delineated. PMNs have long been thought to be critical for efficient staphylococcal clearance (19,22), and the increased incidence of severe staphylococcal infection in humans with disorders of PMN function or activation, such as chronic granulomatous disease (10, 12), confirm this observation. PMNs themselves can also contribute to the pathology associated with staphylococcal infection. A substantial component of the lung pathology associated with S. aureus USA300 pneumonia has been attributed to the PVL-associated release of cytotoxic components from PMN granules (5). In models of soft tissue infection, the importance ...

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