Incompetence of Neutrophils to Invasive Group A streptococcus Is Attributed to Induction of Plural Virulence Factors by Dysfunction of a Regulator

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.

A Synthetic M Protein Peptide Synergizes with a CXC Chemokine Protease To Induce Vaccine-Mediated Protection against Virulent Streptococcal Pyoderma and Bacteremia

“…Activated PMNs can phagocytose and kill GAS (37). Similarly, impaired PMN function, due to failure of PMN migration following CXC chemokine destruction or due to necrosis of PMNs by the pore-forming toxin streptolysin O, results in severe GAS infection (32). In this study, we observed that the efficacy of J8-DT vaccination was ablated in PMN-depleted mice.…”

“…Accessory immune cells are known to play a critical role in protection against streptococci (24,31,32). We show that skin-resident macrophages contribute to the control of bacterial burden in the skin, whereas systemic macrophages contribute to the control of systemic infection.…”

CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants

“…3B, it is seen that genes derepressed in M23ND/CovS Ϫ , viz., hasABC, slo and nga, the mga regulon, spyA, and prtS, are highly associated with invasiveness and antiphagocytosis, which are important for deeper colonization and resistance to neutrophil killing of GAS. Previous studies also showed that these genes have higher expression in invasive GAS infections than in noninvasive infections (3,5,47), and expression of the genes is considered essential for evasion, persistence, and/or dissemination (48)(49)(50). Remarkably, the highly elevated expression of the hasABC operon played a key role in resistance to host killing in invasive infections of GAS.…”

Description of the Pathogenic Features of <i>Streptococcus pyogenes</i> Isolates from Invasive and Non-Invasive Diseases in Aichi, Japan

“…Hypervirulent S. pyogenes of the emm1 genotype has recently been associated with more severe invasive diseases (3). According to previous investigations (2)(3)(4)(5), emm1 hypervirulent S. pyogenes is defined by the abundant production of numerous virulence factors such as the superantigen, streptococcal exotoxin A (SpeA), the nuclease, streptococcal DNase (Sda1), the cytotoxin nicotinamide adenine dinucleotide (NAD)-glycohydrolase (NADase), and the hemolysin streptolysin O (SLO), but not the proteinase streptococcal exotoxin B (SpeB). The phenotype is mostly explained by mutations in the covR/S genes that comprise a two-component signal transduction system that affects the expression of up to 15z of S. pyogenes genes, including many expressing virulence factors (4).…”

“…S. pyogenes commonly causes pharyngitis among schoolchildren, as well as invasive diseases such as sepsis and streptococcal toxic shock syndrome (STSS), which have become more prevalent globally during the last 25 years. STSS is associated with symptoms of hypotension, renal impairment, disseminated intravascular coagulopathy, liver involvement, adult respiratory distress syndrome, generalized erythematous macular rash, soft tissue necrosis, and central nervous disorders, and mortality rates range from 30z to 70z (1,2). Hypervirulent S. pyogenes of the emm1 genotype has recently been associated with more severe invasive diseases (3).…”