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Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity
Fadie T Coleman1,2, Matthew T Blahna1, Hirofumi Kamata1
1Pulmonary Center.
Abstract:
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.
Insights
Certain pneumococci strains can evade immune responses by suppressing nuclear factor κB (NF-κB) activation in macrophages, leading to more severe pneumonia. Enhancing NF-κB activation may offer a new therapeutic strategy.
Area of Science:
- Infectious Diseases
- Immunology
- Microbiology
Background:
- Pneumococcal pneumonia defense relies on innate immunity, particularly alveolar macrophages and nuclear factor κB (NF-κB) activation.
- Streptococcus pneumoniae may evolve to evade or subvert macrophage NF-κB activation, potentially influencing disease severity.
Purpose of the Study:
- To investigate the diversity of Streptococcus pneumoniae's ability to activate macrophage NF-κB.
- To determine the association between varying NF-κB activation levels and pneumonia complexity.
- To explore the therapeutic potential of modulating macrophage NF-κB activation in pneumococcal pneumonia.
Main Methods:
- Analysis of Streptococcus pneumoniae isolates from children with pneumonia in Massachusetts.
- Assessment of macrophage NF-κB activation levels induced by different pneumococcal strains.
- In vivo mouse models to evaluate the severity of lung infections caused by low vs. high NF-κB activating pneumococci.
- Investigation of macrophage cell fate, including necroptosis, in response to pneumococcal NF-κB activation.
Main Results:
- Pneumococcal activation of macrophage NF-κB is diverse, with many strains identified as low NF-κB activators.
- Low NF-κB activating pneumococci are associated with complicated pneumonia and cause more severe lung infections in mice.
- Low NF-κB activators promote a detrimental necroptosis pathway in macrophages, which can be reversed by high NF-κB activators.
Conclusions:
- Low NF-κB activation by Streptococcus pneumoniae represents a significant virulence factor.
- Appropriate activation of macrophage NF-κB is crucial for effective antibacterial defense against pneumococcal pneumonia.
- Modulating macrophage NF-κB activation holds promise as an adjunctive therapy for pneumococcal pneumonia.