Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity.

During pneumococcal pneumonia, antibacterial defense requires the orchestrated expression of innate immunity mediators, initiated by alveolar macrophages and dependent on transcription driven by nuclear factor κB (NF-κB). Such immune pressure may select for pneumococci, which avoid or subvert macrophage NF-κB activation. Analyzing pneumococci collected from children in Massachusetts, we found that the activation of macrophage NF-κB by Streptococcus pneumoniae is highly diverse, with a preponderance of low NF-κB activators that associate particularly with complicated pneumonia. Low NF-κB activators cause more severe lung infections in mice, and they drive macrophages toward an alternate and detrimental cell fate of necroptosis. Both outcomes can be reversed by activation of macrophages with pneumococci that are high NF-κB activators. These results suggest that low NF-κB activation is a virulence property of pneumococci and that the appropriate activation of macrophages, including NF-κB, may hold promise as an adjunct therapeutic avenue for pneumococcal pneumonia.

Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia.

Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. To differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from three sorted cell populations: epithelial cells from uninfected mouse lungs, epithelial cells from mouse lungs with pneumococcal pneumonia, and nonepithelial cells from those same infected lungs. Of 1,166 transcripts that were more abundant in epithelial cells from infected lungs compared with nonepithelial cells from the same lungs or from epithelial cells of uninfected lungs, 32 genes were identified as highly expressed secreted products. Especially strong signals included two related secreted and transmembrane (Sectm) 1 genes, Sectm1a and Sectm1b. Refinement of sorting strategies suggested that both Sectm1 products were induced predominantly in conducting airway epithelial cells. Sectm1 was induced during the early stages of pneumococcal pneumonia, and mutation of NF-κB RelA in epithelial cells did not diminish its expression. Instead, type I IFN signaling was necessary and sufficient for Sectm1 induction in lung epithelial cells, mediated by signal transducer and activator of transcription 1. For target cells, Sectm1a bound to myeloid cells preferentially, in particular Ly6G(bright)CD11b(bright) neutrophils in the infected lung. In contrast, Sectm1a did not bind to neutrophils from uninfected lungs. Sectm1a increased expression of the neutrophil-attracting chemokine CXCL2 by neutrophils from the infected lung. We propose that Sectm1a is an epithelial product that sustains a positive feedback loop amplifying neutrophilic inflammation during pneumococcal pneumonia.