TY - JOUR
T1 - Streptolysin O rapidly impairs neutrophil oxidative burst and antibacterial responses to Group A Streptococcus
AU - Uchiyama, Satoshi
AU - Döhrmann, Simon
AU - Timmer, Anjuli M.
AU - Dixit, Neha
AU - Ghochani, Mariam
AU - Bhandari, Tamara
AU - Timmer, John C.
AU - Sprague, Kimberly
AU - Bubeck-Wardenburg, Juliane
AU - Simon, Scott I.
AU - Nizet, Victor
N1 - Publisher Copyright:
© 2015 Uchiyama, Döhrmann, Timmer, Dixit, Ghochani, Bhandari, Timmer, Sprague, Bubeck-Wardenburg, Simon and Nizet.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Group A Streptococcus
KW - Infection
KW - Neutrophil extracellular traps
KW - Neutrophils
KW - Oxidative burst
KW - Pore-forming toxin
KW - Streptococcus pyogenes
KW - Streptolysin O
UR - http://www.scopus.com/inward/record.url?scp=84949549336&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2015.00581
DO - 10.3389/fimmu.2015.00581
M3 - Article
AN - SCOPUS:84949549336
SN - 1664-3224
VL - 6
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - NOV
M1 - 581
ER -