title: Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus.
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 (<30 min), contributing to GAS escape from neutrophil clearance.
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uchiyama
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Döhrmann
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Anjuli M
authors.initials: AM
authors.lastname: Timmer
authors.affiliation: Department of Biomedical Engineering, University of California Davis , Davis, CA , USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Dixit
authors.affiliation: Department of Biological Sciences, San Diego State University , San Diego, CA , USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Ghochani
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Bhandari
authors.affiliation: Department of Pharmacology, University of California San Diego , La Jolla, CA , USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Timmer
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sprague
authors.affiliation: Department of Pediatrics, University of Chicago , Chicago, IL , USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck-Wardenburg
authors.affiliation: Department of Biomedical Engineering, University of California Davis , Davis, CA , USA.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Simon
authors.affiliation: Department of Pediatrics, University of California San Diego , La Jolla, CA , USA ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, CA , USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
keywords: Streptococcus pyogenes; group A Streptococcus; infection; neutrophil extracellular traps; neutrophils; oxidative burst; pore-forming toxin; streptolysin O