Streptolysin O rapidly impairs neutrophil oxidative burst and antibacterial responses to Group A Streptococcus

Satoshi Uchiyama, Simon Döhrmann, Anjuli M. Timmer, Neha Dixit, Mariam Ghochani, Tamara Bhandari, John C. Timmer, Kimberly Sprague, Juliane Bubeck-Wardenburg, Scott I. Simon, Victor Nizet

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here, we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and early time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps, cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (

Original languageEnglish (US)
Article number581
JournalFrontiers in Immunology
Volume6
Issue numberNOV
DOIs
StatePublished - 2015

Keywords

  • Group A Streptococcus
  • Infection
  • Neutrophil extracellular traps
  • Neutrophils
  • Oxidative burst
  • Pore-forming toxin
  • Streptococcus pyogenes
  • Streptolysin O

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Uchiyama, S., Döhrmann, S., Timmer, A. M., Dixit, N., Ghochani, M., Bhandari, T., Timmer, J. C., Sprague, K., Bubeck-Wardenburg, J., Simon, S. I., & Nizet, V. (2015). Streptolysin O rapidly impairs neutrophil oxidative burst and antibacterial responses to Group A Streptococcus. Frontiers in Immunology, 6(NOV), [581]. https://doi.org/10.3389/fimmu.2015.00581