Abstract
Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection.
Highlights
IntroductionStreptococcus pyogenes (group A streptococcus; Group A streptococcus (GAS)) is one of the most common human pathogens
Streptococcus pyogenes is one of the most common human pathogens
In parallel with the expression profile of slo and scpC in the severe invasive Group A streptococcus (GAS), introduction of the intact csrS gene into the severe invasive GAS restored the susceptibility to the killing by polymorphnuclear neutrophils (PMN) (p = 0.015 compared with severe invasive isolates +CsrS) (Figure 6A), abrogated the inhibition of PMN migration by degradation of IL-8 (p = 0.002 compared with invasive isolates +CsrS) (Figure 4A, 4B, and 6B), and diminished the killing activity for PMN by necrosis (p = 0.00016 compared with invasive isolates +CsrS) (Figure 3A, 3C, and 6C), These results strongly suggest that mutations in the csrS gene correspond to the immunocompromized activity in the severe invasive isolates, associated with inhibition of PMN recruitment and survival
Summary
Streptococcus pyogenes (group A streptococcus; GAS) is one of the most common human pathogens. It causes a wide variety of infections ranging from uncomplicated pharyngitis and skin infections to severe and even life-threatening manifestations, such as necrotizing fasciitis (NF) and streptococcal toxic shock-like syndrome (STSS) [1,2], with high mortality rates ranging from 20% to 60% [3]. Which of factors are involved in pathogenesis mediated by clinically isolated severe invasive GAS remains obscure. The strains of emm genotype, among more than 100 emm genes encoding the serotype-determinant M protein, are the predominant cause of severe GAS infections in Japan [7]. Emm GAS isolated from invasive infections seems to acquire the novel or altered virulence factors by mutations, genomic additions, or deletions
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