The Classical Lancefield Antigen of Group A Streptococcus Is a Virulence Determinant with Implications for Vaccine Design

Abstract

SUMMARY 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-L. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAcside 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 its understanding has implications for vaccine development.

GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP‐4‐dehydrorhamnose reductases (RmlD)

“…In contrast to the rmlD genes in other species like Shigella flexneri (Macpherson et al ., 1994) and Streptococcus pneumoniae serotype 19F (Morona et al ., 1997), the only GAS rmlD homologue gacA is not part of an rmlABCD rhamnose biosynthesis operon. Instead, gacA is located at the beginning of the recently identified GAC gene cluster and hence named gacA (van Sorge et al ., 2014). A similar split genomic architecture of the rhamnose biosynthesis genes rmlA‐C and rmlD was previously observed in Streptococcus mutans ( S. mutans ), a cariogenic Gram‐positive bacterium (Tsukioka et al ., 1997).…”

“…However, we were unable to obtain mutants on multiple attempts, suggesting that gacA is essential for GAS (van Sorge et al ., 2014). Additional proof for potential essentiality of gacA was investigated as part of a larger screen for essential genes in GAS using the mariner transposon Krmit (Le Breton et al ., 2015).…”

“…From targeted mutagenesis attempts and Tn‐Seq studies, we conclude that gacA is essential for growth of GAS in rich medium, in agreement to a previous study that suggested that gacA might be essential (van Sorge et al ., 2014). We validated that gacA is essential by a riboswitch‐inducible expression system resulting in attenuated growth and severe cellular abnormalities in the absence of gacA .…”

“…Recently, van Sorge et al . (2014) identified the gene cluster responsible for GAC biosynthesis and demonstrated that the GAC GlcNAc side‐chain contributes to GAS virulence.…”

The Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms and Preeclampsia Susceptibility

“…Preeclampsia is diagnosed when hypertension and one of the following criteria are present: proteinuria (≥ 300 mg/24 h) or a urine protein-to-creatinine ratio ≥ 0.3, or dipstick 1 + persistent proteinuria, thrombocytopenia (PLT < 100000/µL), kidney insufficiency (creatinine > 1.1 mg/dL or doubling of baseline), liver involvement (serum transaminases level ≥ twice normal), cerebral symptoms (headache, visual disturbances, convulsions), pulmonary edema. Hypertension attributable to pregnancy should resolve within 12 weeks after delivery (2). In addition, neonatal complications of Preeclampsia include prematurity, fetal growth restriction, neurologic damage (hypoxia related) and perinatal death.…”