The rise and spread of invasive emm49 Streptococcus pyogenes in the USA

<b>Background.</b> The propensity of <i>Streptococcus pyogenes</i> (group A <i>Streptococcus</i>) to invade normally sterile sites and cause invasive group A <i>Streptococcus</i> (iGAS) disease varies across strains, which are classified using the <i>emm</i> gene. Between 2015 and 2017, multistate iGAS surveillance identified an ~150-fold increase of one particular <i>emm</i> type, <i>emm</i>49. This genomic epidemiological analysis aimed to identify bacterial, patient and societal factors associated with this expansion.<b>Methods.</b> We analysed 1322 <i>emm</i>49 iGAS cases and the genome sequences of the clinical isolates acquired through the population-based Active Bacterial Core surveillance during 2015-2022. For each invasive case, we received both a cultured isolate and a standardized case report form that included basic demographic attributes and risk factors of infection. A phylogeographic analysis was performed to reconstruct the divergence times and spatial dispersal history within our <i>emm</i>49 collection.<b>Results.</b> Compared to other <i>emm</i> types, <i>emm</i>49 cases were more common in males (63.5% vs. 58.3%, <i>P</i>=0.0143), in people experiencing homelessness (34.0% vs. 17.5%, <i>P</i><0.0001) and in people who inject drugs (23.7% vs. 13.1%, <i>P</i><0.0001). Time-scaled phylogeographic analysis estimated that the most recent common ancestor of the post-2015 expansion isolates occurred around 2004 and that <i>emm</i>49 emerged in the western USA.<b>Conclusion.</b> Our findings suggest that the current nationwide outbreak may have originated from the introduction of <i>emm</i>49 into disadvantaged (homeless and/or injecting drug users) adult subpopulations. This study underscores how social marginalization and broader social determinants of health can shape iGAS strain epidemiology in the USA.