Seminar: Dr. Nina van Sorge

Modification of the streptococcal Lancefield carbohydrate yields a universal vaccine

Date:
20 November 2012 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Modification of the streptococcal Lancefield carbohydrate yields a universal vaccine
Speaker(s):

Dr. Nina van Sorge, University of Utrecht

Host(s):

Dr. Annemiek van Spriel, Department of Tumor Immunology, NCMLS Nijmegen

20-11-2012 00:00:00Europe/AmsterdamModification of the streptococcal Lancefield carbohydrate yields a universal vaccine Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

Sorge van, NinaGroup A Streptococcus (GAS;Streptococcus pyogenes) is a preeminent human pathogen ranking among the top 10 infection-related causes of mortality worldwide. GAS is defined by the expression of a unique carbohydrate structure called the group A carbohydrate (GAC; Lancefield antigen). Comprising ~50% of the dry weight of the bacterial cell wall, GAC consists of a polyrhamnose backbone and an immunodominant N‑acetylglucosamine (GlcNAc) side chain. A safe and efficacious GAS vaccine has yet be developed, a goal made more challenging by the >150 different serotypes based on the immunovariable surface M protein. GAC has shown potential as a universal GAS vaccine in animal studies, but safety concerns were raised since the GlcNAc side chain is implicated in the immunopathogenesis of post-infectious acute rheumatic fever. Using bioinformatics and molecular genetics, we discovered the genetic locus responsible for GAC biosynthesis and generated a viable mutant that lacks the GlcNAc side chain. The mutation did not affect GAS growth or expression of know virulence factors; however, surface charge, hydrophobicity, and chain length were altered compared to the parent strain. Lack of the GlcNAc side chain attenuated streptococcal virulence in two animal infection models, identifying the GlcNAc side chain as a novel GAS virulence factor.In vitrostudies showed diminished survival of mutant bacteria in the presence of whole blood, neutrophils and serum. Importantly, passive immunization with antibodies raised against the GlcNAc-deficient polysaccharide enhanced neutrophil killingin vitroand protected mice from challenge with wild-type GAS, indicating the mutant GAC is a promising universal vaccine antigen devoid of risk for autoimmune complications.

 

 



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