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.
Highlights
The Gram-positive bacterium group A Streptococcus (GAS; Streptococcus pyogenes) is a leading human pathogen ranked among the top 10 causes of infection-associated mortality worldwide [1]
GAS M1T1 strains can undergo a spontaneous mutation in the two component global regulatory system covR/S in vivo leading to upregulation of capsule, nuclease, and other GAS virulence factors [15, 16], and neutrophil resistance may be an important selection pressure for the survival and bloodstream dissemination of these mutants [17]
As each bacterial species is replete with pathogen-associated molecular patterns to stimulate neutrophil activation, we hypothesized that GAS produced factor(s) that suppressed the full host oxidative burst potential
Summary
The Gram-positive bacterium group A Streptococcus (GAS; Streptococcus pyogenes) is a leading human pathogen ranked among the top 10 causes of infection-associated mortality worldwide [1]. An estimate of 5–15% of all humans are colonized with GAS, which can cause a wide spectrum of infections ranging from self-limiting pharyngitis and impetigo to invasive and GAS SLO Blunts Neutrophil Responses life-threatening diseases including streptococcal toxic shock syndrome and necrotizing fasciitis [2]. GAS M1T1 strains can undergo a spontaneous mutation in the two component global regulatory system covR/S ( known as csrR/S) in vivo leading to upregulation of capsule, nuclease, and other GAS virulence factors [15, 16], and neutrophil resistance may be an important selection pressure for the survival and bloodstream dissemination of these mutants [17]
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