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Induction of Krüppel-Like Factor 4 Mediates Polymorphonuclear Neutrophil Activation in Streptococcus pneumoniae
Aritra Bhattacharyya1, Toni Herta1, Claudia Conrad1
1Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Abstract:
The recruitment and activation of polymorphonuclear neutrophils (PMNs) are of central importance for the elimination of pathogens in bacterial infections. We investigated the Streptococcus pneumoniae-dependent induction of the transcription factor Krüppel-like factor (KLF) 4 in PMNs as a potential regulator of PMN activation. We found that KLF4 expression is induced in human blood-derived PMNs in a time- and dose-dependent manner by wild-type S. pneumoniae and capsule knockout mutants. Unencapsulated knockout mutants induced stronger KLF4 expression than encapsulated wild types. The presence of autolysin LytA-competent (thus viable) pneumococci and LytA-mediated bacterial autolysis were required for KLF4 induction in human and murine PMNs. LyzMcre-mediated knockdown of KLF4 in murine blood-derived PMNs revealed that KLF4 influences pneumococci killing and increases the release of the proinflammatory cytokines tumor necrosis factor α and keratinocyte chemoattractant and decreases the release of the anti-inflammatory cytokine interleukin-10. Thus, S. pneumoniae induces KLF4 expression in PMNs, which contributes to PMN activation in S. pneumoniae infection.
Insights
Streptococcus pneumoniae induces Krüppel-like factor 4 (KLF4) in polymorphonuclear neutrophils (PMNs). This KLF4 induction is essential for effective bacterial killing and modulating inflammatory responses during pneumococcal infections.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Polymorphonuclear neutrophils (PMNs) are crucial for combating bacterial infections.
- Understanding the molecular mechanisms regulating PMN activation is vital for treating infections like those caused by Streptococcus pneumoniae.
Purpose of the Study:
- To investigate the role of Krüppel-like factor 4 (KLF4) in Streptococcus pneumoniae-induced PMN activation.
- To determine the signaling pathways involved in KLF4 induction by S. pneumoniae.
Main Methods:
- Quantification of KLF4 expression in human and murine PMNs stimulated with S. pneumoniae.
- Analysis of KLF4 induction by wild-type and mutant S. pneumoniae strains (e.g., capsule knockout, LytA mutants).
- Assessment of PMN functions, including bacterial killing and cytokine release, following KLF4 knockdown in murine models.
Main Results:
- S. pneumoniae time- and dose-dependently induces KLF4 expression in PMNs.
- LytA-competent pneumococci and bacterial autolysis are required for KLF4 induction.
- Unencapsulated S. pneumoniae mutants induced higher KLF4 levels than encapsulated wild-type strains.
- KLF4 knockdown in mice impaired pneumococci killing and altered the release of pro- and anti-inflammatory cytokines (TNF-α, KC, IL-10).
Conclusions:
- S. pneumoniae actively induces KLF4 expression in PMNs.
- KLF4 plays a significant role in regulating PMN-mediated bacterial clearance and inflammatory responses during pneumococcal infections.
- Targeting KLF4 may offer a therapeutic strategy for enhancing host defense against S. pneumoniae.
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