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

Background. The propensity of Streptococcus pyogenes (group A Streptococcus) to invade normally sterile sites and cause invasive group A Streptococcus (iGAS) disease varies across strains, which are classified using the emm gene. Between 2015 and 2017, multistate iGAS surveillance identified an ~150-fold increase of one particular emm type, emm49. This genomic epidemiological analysis aimed to identify bacterial, patient and societal factors associated with this expansion.Methods. We analysed 1322 emm49 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 emm49 collection.Results. Compared to other emm types, emm49 cases were more common in males (63.5% vs. 58.3%, P=0.0143), in people experiencing homelessness (34.0% vs. 17.5%, P<0.0001) and in people who inject drugs (23.7% vs. 13.1%, P<0.0001). Time-scaled phylogeographic analysis estimated that the most recent common ancestor of the post-2015 expansion isolates occurred around 2004 and that emm49 emerged in the western USA.Conclusion. Our findings suggest that the current nationwide outbreak may have originated from the introduction of emm49 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.