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Invasive group A Streptococcus disease in French-Canadian children is not associated with a defect in MyD88/IRAK4-pathway.

Fernandez I, Brito RM, Bidet P, Rallu F, Laferrière C, Ovetchkine P, Le Deist F - Allergy Asthma Clin Immunol (2014)

Bottom Line: Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected.Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host's innate immune response.Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, Infectiology and Immunology, CHU Sainte-Justine and University of Montreal, Montreal (Quebec), Canada. isabel.fernandez.hsj@ssss.gouv.qc.ca.

ABSTRACT

Background: Beta-hemolytic Group A Streptococcus invasive disease (iGASd) has been subject to intense research since its re-emergence in the late 1980s. In Quebec, an increase in the number of severe iGASd cases has recently been observed. Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected. Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host's innate immune response.

Methods: In this report, we assessed the influence of: (i) bacterial genotype and virulence factors, (ii) immune-cellular features, and (iii) Myd88/IRAK4-dependent response to GAS in vitro on the susceptibility to iGASd in a paediatric cohort of 16 children: 11 French-Canadian and 5 from diverse origin.

Findings: GAS virulence factors and genotype are not implicated in the susceptibility toward iGASd, and cellular and MyD88/IRAK4 deficiencies are excluded in our patients.

Conclusions: Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.

No MeSH data available.


Related in: MedlinePlus

In vitro secretion of cytokines (TNF-α, IL-6, and IL-10) after 24 h of TLR-stimulation of whole blood (1/5 dilution). Results in patients (●) are expressed as mean of secretion calculated as (secretion in activated -secretion in non stimulated cells) from duplicate results. Not statistically significant differences between healthy individuals and patients were found (Mann–Whitney non-parametric test). Box: 5–95% percentile; Whiskers: Range; ▬ median in healthy controls.
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Figure 1: In vitro secretion of cytokines (TNF-α, IL-6, and IL-10) after 24 h of TLR-stimulation of whole blood (1/5 dilution). Results in patients (●) are expressed as mean of secretion calculated as (secretion in activated -secretion in non stimulated cells) from duplicate results. Not statistically significant differences between healthy individuals and patients were found (Mann–Whitney non-parametric test). Box: 5–95% percentile; Whiskers: Range; ▬ median in healthy controls.

Mentions: To assess a hypothetical MyD88/IRAk4 signalling defect, a functional study was performed after Toll-like receptor (TLR)-4 (LPS from Salmonella enterica) and TLR-2 (LTA from Saccharomyces Cerevisia), TLR-2/TLR-6 heterodimers (lipopeptide Pam2CSK4), and TLR-2/TLR-1 heterodimers (lipopeptide Pam3CSK4) activation in presence of polymyxin B, as previously described [6]. After 1 h incubation, CD62L cleavage on granulocytes was evaluated by flow cytometry (FACScanto cytometer, Becton Dickinson) and after 24 h, IL-6, TNF-α, and IL-10 secretion was assessed by ELISA. Intriguingly, no defective TLR-dependent response was observed for CD62L cleavage (Additional file 1: Table S3), nor in cytokine secretion (Figure 1) (Mann–Whitney non-parametric test).


Invasive group A Streptococcus disease in French-Canadian children is not associated with a defect in MyD88/IRAK4-pathway.

Fernandez I, Brito RM, Bidet P, Rallu F, Laferrière C, Ovetchkine P, Le Deist F - Allergy Asthma Clin Immunol (2014)

In vitro secretion of cytokines (TNF-α, IL-6, and IL-10) after 24 h of TLR-stimulation of whole blood (1/5 dilution). Results in patients (●) are expressed as mean of secretion calculated as (secretion in activated -secretion in non stimulated cells) from duplicate results. Not statistically significant differences between healthy individuals and patients were found (Mann–Whitney non-parametric test). Box: 5–95% percentile; Whiskers: Range; ▬ median in healthy controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3927219&req=5

Figure 1: In vitro secretion of cytokines (TNF-α, IL-6, and IL-10) after 24 h of TLR-stimulation of whole blood (1/5 dilution). Results in patients (●) are expressed as mean of secretion calculated as (secretion in activated -secretion in non stimulated cells) from duplicate results. Not statistically significant differences between healthy individuals and patients were found (Mann–Whitney non-parametric test). Box: 5–95% percentile; Whiskers: Range; ▬ median in healthy controls.
Mentions: To assess a hypothetical MyD88/IRAk4 signalling defect, a functional study was performed after Toll-like receptor (TLR)-4 (LPS from Salmonella enterica) and TLR-2 (LTA from Saccharomyces Cerevisia), TLR-2/TLR-6 heterodimers (lipopeptide Pam2CSK4), and TLR-2/TLR-1 heterodimers (lipopeptide Pam3CSK4) activation in presence of polymyxin B, as previously described [6]. After 1 h incubation, CD62L cleavage on granulocytes was evaluated by flow cytometry (FACScanto cytometer, Becton Dickinson) and after 24 h, IL-6, TNF-α, and IL-10 secretion was assessed by ELISA. Intriguingly, no defective TLR-dependent response was observed for CD62L cleavage (Additional file 1: Table S3), nor in cytokine secretion (Figure 1) (Mann–Whitney non-parametric test).

Bottom Line: Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected.Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host's innate immune response.Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, Infectiology and Immunology, CHU Sainte-Justine and University of Montreal, Montreal (Quebec), Canada. isabel.fernandez.hsj@ssss.gouv.qc.ca.

ABSTRACT

Background: Beta-hemolytic Group A Streptococcus invasive disease (iGASd) has been subject to intense research since its re-emergence in the late 1980s. In Quebec, an increase in the number of severe iGASd cases has recently been observed. Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected. Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host's innate immune response.

Methods: In this report, we assessed the influence of: (i) bacterial genotype and virulence factors, (ii) immune-cellular features, and (iii) Myd88/IRAK4-dependent response to GAS in vitro on the susceptibility to iGASd in a paediatric cohort of 16 children: 11 French-Canadian and 5 from diverse origin.

Findings: GAS virulence factors and genotype are not implicated in the susceptibility toward iGASd, and cellular and MyD88/IRAK4 deficiencies are excluded in our patients.

Conclusions: Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.

No MeSH data available.


Related in: MedlinePlus