Neutralization of Streptolysin S-Dependent and Independent Inflammatory Cytokine IL-1β Activity Reduces Pathology During Early Group A Streptococcal Skin Infection

Frontiers in Cellular and Infection Microbiology

Jessica N. Ross²  Rebecca A. Flaherty²  Katelyn E. Carothers²  Francis J. Castellino³  Deborah L. Donahue³  Victoria A. Ploplis³  Shaun W. Lee³ 

[1] Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States;Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, United States;W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN, United States;

关键词: Streptolysin S;    host-pathogen interactions;    inflammatory signaling;    p38 MAPK;    cytokine;    interleukin-1 beta;   

DOI  :  10.3389/fcimb.2018.00211

来源: DOAJ

【 摘 要 】

The bacterial pathogen Group A Streptococcus (GAS) has been shown to induce a variety of human diseases ranging in severity from pharyngitis to toxic shock syndrome and necrotizing fasciitis. GAS produces a powerful peptide toxin known as Streptolysin S (SLS). Though long recognized as a potent cytolysin, recent evidence from our lab has shown that SLS-dependent cytotoxicity is mediated through activation of the pro-inflammatory mediators p38 MAPK and NFκB. These findings led us to hypothesize that activation of p38 MAPK and NFκB signaling drive the production of pro-inflammatory cytokines which, in turn, serve as positive feedback signals to initiate cytotoxicity in infected host cells. To address this hypothesis, we utilized a cytokine array to characterize the SLS-dependent pro-inflammatory cytokine response to GAS infection in human keratinocytes. From these studies, IL-1β was found to be markedly upregulated in the presence of SLS, and further investigation revealed that this cytokine contributes to cytotoxicity in human keratinocytes during infection. Subcutaneous infection studies were performed in mice to address the physiological impact of increased IL-1β production. These studies demonstrated that IL-1β is produced during GAS skin infection in an SLS-dependent manner. Furthermore, inhibition of this cytokine and the upstream kinases and other signaling mediators that drive its production reduced SLS-mediated lesion formation early in the infection process. Together, our findings indicate that pharmacological inhibition of this inflammatory axis holds promise as a therapeutic strategy to reduce tissue destruction during severe invasive Group A Streptococcal infections.

【 授权许可】

Unknown