van Sorge NM, Cole JN, Kuipers K, Henningham A, Aziz RK, Kasirer-Friede A, Lin L, Berends ET, Davies MR, Dougan G, Zhang F, Dahesh S, Shaw L, Gin J, Cunningham M, Merriman JA, Hütter J, Lepenies B, Rooijakkers SH, Malley R, Walker MJ, Shattil SJ, Schlievert PM, Choudhury B, Nizet V. Cell Host Microbe. 2014 Jun 11;15(6):729-40. doi: 10.1016/j.chom.2014.05.009. PMID: 24922575
Group A Streptococcus (GAS) is a leading cause of infection-related mortality in humans. All GAS serotypes express the Lancefield group A carbohydrate (GAC), comprising a polyrhamnose backbone with an immunodominant N-acetylglucosamine (GlcNAc) side chain, which is the basis of rapid diagnostic tests. No biological function has been attributed to this conserved antigen. Here we identify and characterize the GAC biosynthesis genes, gacA through gacL. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37. Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization. Thus, the Lancefield antigen plays a functional role in GAS pathogenesis, and a deeper understanding of this unique polysaccharide has implications for vaccine development.