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Characterization of Inflammatory Responses During Intranasal Colonization with Streptococcus pneumoniae
Published on: January 17, 2014
Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract
Dane Parker1, Francis J Martin, Grace Soong
1Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA. dp2375@columbia.edu
Unlabelled:
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.
Importance:
The bacterium Streptococcus pneumoniae is a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clear S. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen.
Insights
The bacterium Streptococcus pneumoniae activates type I interferon (IFN) signaling in the airway, crucial for clearing infections. This response, mediated by pneumolysin, highlights IFN
Area of Science:
- Immunology
- Microbiology
- Respiratory Medicine
Background:
- The mucosal epithelium is the primary defense against respiratory pathogens.
- Type I interferon (IFN) signaling is traditionally linked to antiviral responses.
- The sensing mechanisms of the mucosal epithelium against bacterial pathogens remain unclear.
Purpose of the Study:
- To investigate how the airway mucosal epithelium senses the extracellular bacterium Streptococcus pneumoniae.
- To determine the role of type I IFN signaling in response to S. pneumoniae infection.
- To elucidate the bacterial components and host pathways involved in this response.
Main Methods:
- Utilized mouse models, including wild-type and knockout mice (Tlr4-/-, Myd88-/-, Trif-/-, Nod2-/-, IFN-α/β receptor null).
- Investigated the role of pneumolysin and bacterial DNA in activating IFN-β expression via the DAI/STING/TBK1/IRF3 pathway.
- Assessed S. pneumoniae nasal colonization levels in different mouse models.
Main Results:
- Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells.
- Pneumolysin, a pore-forming toxin, is essential for this IFN response.
- Pneumococcal DNA triggers IFN-β expression through the DAI/STING/TBK1/IRF3 signaling pathway.
- Mice lacking Tlr4, Myd88, Trif, or Nod2 showed no impairment in type I IFN signaling.
- Mice lacking the type I IFN receptor exhibited increased S. pneumoniae nasal colonization, indicating impaired clearance.
Conclusions:
- The type I IFN cascade is a critical component of the mucosal immune response to airway bacterial pathogens like S. pneumoniae.
- Extracellular bacteria can activate intracellular pattern recognition pathways, typically associated with viral immunity.
- Pneumolysin and bacterial DNA are key pathogen-associated molecular patterns (PAMPs) that engage intracellular receptors to initiate the type I IFN response.
- Type I IFNs are essential for controlling S. pneumoniae colonization and facilitating pathogen eradication from the airways.
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