Influence of macrophage NF-kappaB activation on pneumococcal pneumonia

Streptococcus pneumoniae (pneumococcus) is commonly found in the nasopharynx of healthy individuals, yet it can be a serious pathogen, particularly in the lower respiratory tract, where it can cause severe pneumonia. During pneumococcal pneumonia, anti-bacterial host defense requires the orchestrated expression of innate immunity mediators, initiated by alveolar macrophages and dependent on transcriptional activity driven by Nuclear Factor-B (NF-B). Although the initiation of a pulmonary inflammatory response is critical to anti-pneumococcal defense during pneumonia, how differences in pneumococcal-macrophage interactions can influence this process is unclear. To determine the functional significance of varying macrophage NF-B activation, we examined macrophage responses to pneumococcal stimulation in culture and in mice. Macrophage-pneumococcal interactions resulted in the induction of varied NF-B activation. Two main pathways were revealed regarding host response and disease outcome. Pneumococci that induced efficient macrophage NF-B activation resulted in robust anti-pneumococcal lung defense and bacterial clearance. Conversely, failure to activate effective macrophage NF-B signaling resulted in an altered macrophage response of necroptosis. Overall, we conclude that varying levels of macrophage NF-B activation by pneumococcus can directly influence the severity of infection. Furthermore, inefficient macrophage NF-B activation can also have cytotoxic effects on these critical lung resident cells during pneumonia. The induction of macrophage NF-B activation by S. pneumoniae is as diverse as the population of pneumococcal isolates in the community. A unique host-pathogen interaction exists between pneumococcus and the alveolar macrophage that plays an important role in anti-pneumococcal defense during pneumonia and in the prevention of cytotoxic consequences induced by virulent pneumococci. This interaction suggests that therapies, which modulate NF-B activation, hold promise for augmenting resistance and ameliorating deleterious effects during pneumococcal pneumonia that could lead to the development of severe disease