Induction of Krüppel-Like Factor 4 Mediates Polymorphonuclear Neutrophil Activation in Streptococcus pneumoniae Infection.

Aritra Bhattacharyya,Toni Herta,Claudia Conrad,Janine Zahlten,Doris Frey,Norbert Suttorp,Pedro García,Stefan Hippenstiel

doi:10.3389/fmicb.2020.582070

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.

Highlights

Streptococcus pneumoniae is the main causative agent of community-acquired pneumonia and meningitis in children younger than 5 years and adults older than 65 years (van de Beek et al, 2006; Pletz et al, 2012; Prina et al, 2015)
We previously showed that S. pneumoniae induces KLF4 in murine macrophages via TLR9, the Toll-like receptors (TLRs) adapter proteins MyD88 and TRIF, and a hitherto unknown host cell DNA sensor (Herta et al, 2018)
The induction mechanism in polymorphonuclear neutrophils (PMNs) is partly similar to the one we described in macrophages (Herta et al, 2018) and epithelial cells (Zahlten et al, 2013, 2015); in all cell types, autolysin LytA-mediated bacterial autolysis was necessary to induce KLF4

Summary

Introduction

Streptococcus pneumoniae is the main causative agent of community-acquired pneumonia and meningitis in children younger than 5 years and adults older than 65 years (van de Beek et al, 2006; Pletz et al, 2012; Prina et al, 2015). Different serotypes are responsible for different organ manifestations (Orihuela et al, 2003). The emergence of multidrug-resistant S. pneumoniae strains has increased the mortality and morbidity associated with pneumococcal infections (Van Bambeke et al, 2007). Available pneumococcal vaccines such as the polysaccharide vaccine or the pneumococcal conjugate vaccine provide insufficient. S. pneumoniae is responsible for approximately 40,000 deaths per year in the United States alone (Brooks and Mias, 2018). It is of utmost importance to unveil the molecular mechanism underlying pneumococcal infections to develop new therapeutic strategies

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