DNase Sda1 Allows Invasive M1T1 Group A Streptococcus to Prevent TLR9-Dependent Recognition

Group A Streptococcus (GAS) has developed a broad arsenal of virulence factors that serve to circumvent host defense mechanisms. The virulence factor DNase Sda1 of the hyperinvasive M1T1 GAS clone degrades DNA-based neutrophil extracellular traps allowing GAS to escape extracellular killing. TLR9 is activated by unmethylated CpG-rich bacterial DNA and enhances innate immune resistance. We hypothesized that Sda1 degradation of bacterial DNA could alter TLR9-mediated recognition of GAS by host innate immune cells. We tested this hypothesis using a dual approach: loss and gain of function of DNase in isogenic GAS strains and presence and absence of TLR9 in the host. Either DNA degradation by Sda1 or host deficiency of TLR9 prevented GAS induced IFN-α and TNF-α secretion from murine macrophages and contributed to bacterial survival. Similarly, in a murine necrotizing fasciitis model, IFN-α and TNF-α levels were significantly decreased in wild type mice infected with GAS expressing Sda1, whereas no such Sda1-dependent effect was seen in a TLR9-deficient background. Thus GAS Sda1 suppressed both the TLR9-mediated innate immune response and macrophage bactericidal activity. Our results demonstrate a novel mechanism of bacterial innate immune evasion based on autodegradation of CpG-rich DNA by a bacterial DNase

Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis

BACKGROUND: Rheumatic fever continues to put a significant burden on the health of low socio-economic populations in low and middle-income countries despite the near disappearance of the disease in the developed world over the past century. Antibiotics have long been thought of as an effective method for preventing the onset of acute rheumatic fever following a Group-A streptococcal (GAS) throat infection; however, their use has not been widely adopted in developing countries for the treatment of sore throats. We have used the tools of systematic review and meta-analysis to quantify the effectiveness of antibiotic treatment for sore throat, with symptoms suggestive of group A streptococcal (GAS) infection, for the primary prevention of acute rheumatic fever. METHODS: Trials were identified through a systematic search of titles and abstracts found in the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 4, 2003), MEDLINE (1966–2003), EMBASE (1966–2003), and the reference lists of identified studies. The selection criteria included randomised or quasi-randomised controlled trials comparing the effectiveness of antibiotics versus no antibiotics for the prevention of rheumatic fever in patients presenting with a sore throat, with or without confirmation of GAS infection, and no history of rheumatic fever. RESULTS: Ten trials (n = 7665) were eligible for inclusion in this review. The methodological quality of the studies, in general, was poor. All of the included trials were conducted during the period of 1950 and 1961 and in 8 of the 10 trials the study population consisted of young adult males living on United States military bases. Fixed effects, meta-analysis revealed an overall protective effect for the use of antibiotics against acute rheumatic fever of 70% (RR = 0.32; 95% CI = 0.21–0.48). The absolute risk reduction was 1.67% with an NNT of 53. When meta-analysis was restricted to include only trials evaluating penicillin, a protective effect of 80% was found (Fixed effect RR = 0.20, 95% CI = 0.11–0.36) with an NNT of 60. The marginal cost of preventing one case of rheumatic fever by a single intramuscular injection of penicillin is approximately US$46 in South Africa. CONCLUSION: Antibiotics appear to be effective in reducing the incidence of acute rheumatic fever following an episode of suspected GAS pharyngitis. This effect may be achieved at relatively low cost if a single intramuscular penicillin injection is administered

Inference of Antibiotic Resistance and Virulence among Diverse Group A Streptococcus Strains Using emm Sequencing and Multilocus Genotyping Methods

typing (direct sequencing of the genomic segment coding for the antigenic portion of the M protein) or by multilocus genotyping methods. Phenotype analysis, including critical AbR typing, is generally achieved by much slower and more laborious direct culture-based methods. type and the associated AbR and virulence phenotypes. types

Is susceptibility to chronic rheumatic heart disease determined in early infancy? An analysis of mortality in Britain during the 20th century

Background: The reason why some individuals but not others are susceptible to rheumatic fever and chronic rheumatic heart disease is not understood. Because of the substantial evidence that poverty is an important determinant of the disease and must operate in early life, we have investigated the role of the early environment in an ecological study using 20(th) century mortality as an index of disease prevalence. Methods: We analysed 37,321 deaths from rheumatic heart disease in England and Wales during 1968–78. We compared the geographical distribution of deaths with previous infant mortality records from 1911 onwards. These records included details of mortality at different ages and from different causes. They also included data on housing and population density. Results: Mortality from rheumatic heart disease showed a strong correlation with past infant mortality that was consistently stronger with postneonatal mortality (deaths from one month to one year) than with neonatal mortality (deaths during the first month of life). Areas with high infant mortality from diarrhoea or bronchitis had the highest subsequent mortality from rheumatic heart disease. Although rheumatic heart disease was linked with early overcrowding, regression analyses suggested that overcrowding could not per se explain the infant mortality associations. Conclusions: Chronic rheumatic heart disease may have its origins in early infancy. Our findings raise the possibility that susceptibility to rheumatic fever and rheumatic heart disease may be linked with infection in the postneonatal period. Alternatively, they may be explained by the operation of environmental factors that both predispose to infection in infancy and the subsequent liability to heart disease

Seasonal benzathine penicillin G prophylaxis for recurrent streptococcal pharyngitis in children

WOS: 000074763400012PubMed ID: 9695301Background: To assess the efficacy of benzathine penicillin G (BPG) prophylaxis in recurrent streptococcal pharyngitis in children. Methods: One hundred and sixty children, aged 4-11 years, who experienced at least two episodes of group A beta-hemolytic streptococcal (GABHS) pharyngitis during a 4-month observation period between September and December 1995 were randomly divided into two groups. During the following 4-month period between January and April 1996, 80 children received BPG prophylaxis every 3 weeks as a single intramuscular injection of 1.2 million units for a body weight,greater than 27 kg and a half dose for 27 kg or less. Eighty children were accepted as a control group and were not given BPG prophylaxis. Results: The children in the BPG group experienced significantly less GABHS pharyngitis than those in the control group during the second 4-month period (16 vs 244 episodes, respectively, P < 0.001). BPG prophylaxis decreased streptococcal pharyngitis by 92% in the children in the study group, while the frequency of GABHS pharyngitis was unchanged in those in the control group during the second 4-month period compared with the first 4-month period. Conclusions: The data in the present study demonstrated that intramuscular BPG prophylaxis is very effective in preventing GABHS pharyngitis in children. it is recommended that it is used every 3 weeks in at least the fall-winter seasons in children susceptible to frequent GABHS pharyngitis