Nonencapsulated Group A Streptococcus Associated with Human Invasive Disease (790.1)

Group A Streptococcus (GAS) is a leading human pathogen, causing 650,000 severe invasive diseases annually with 25% mortality. M1 GAS is the most frequently isolated serotype from invasive disease worldwide; however, a recent occurrence of invasive infections in Australia was attributed to M4 GAS. Here, we use a combined molecular genetics and bioinformatics approach to characterize 17 clinical M4 isolates associated with this invasive disease episode. The M4 isolates were classified into 3 pulsed‐field gel electrophoresis groups, and 2 multilocus sequence types. All isolates lacked hyaluronic acid (HA) capsule, a major antiphagocytic virulence factor, and whole genome sequence analysis of 2 isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Most isolates contained mutations within the covRS two‐component regulator, a hallmark of hyperinvasive GAS. Transformation of a plasmid expressing hasABC into M4 GAS restored capsule production. However, encapsulation neither promoted survival in whole human blood, nor enhanced virulence of wild‐type M4 GAS in a mouse model of systemic infection. Bioinformatic analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition by ancestral GAS. Together, these data demonstrate that nonencapsulated GAS is capable of causing life‐threatening invasive human infections.Grant Funding Source: National Health and Medical Research Council of Australia; National Institutes of Health