Population genomic variation in Staphylococcus aureus isolates from carriage and disease in Indigenous communities in the Southwest United States

Indigenous populations in the USA experience disproportionately high rates of <i>Staphylococcus aureus</i> invasive disease, yet the drivers of this disparity remain unclear. To investigate the role of bacterial population structure, we conducted whole-genome sequencing of 589 invasive <i>S. aureus</i> isolates and 125 carriage isolates collected from the Navajo Nation and White Mountain Apache (N/WMA) tribal lands in the Southwest USA. We compared lineage distribution between invasive disease and carriage, and to a contemporaneous set of bloodstream isolates from New Hampshire (NH) (<i>n</i>=377), using a Monte Carlo simulation based on the relative frequency ratio (RFR). Methicillin-resistant <i>S. aureus</i> accounted for 33.4% of invasive infections in N/WMA, and the most prevalent lineages were multi-locus sequence types (STs) 8 and 5. ST8 and ST97 were significantly enriched in invasive disease relative to carriage in N/WMA, suggesting increased invasiveness. Compared to NH, invasive disease in N/WMA was associated with higher frequencies of ST8, ST97 and ST188, while ST5 and ST30 were more common in NH. These findings highlight substantial geographic variation in <i>S. aureus</i> population structure and suggest that lineage composition may contribute to the elevated burden of invasive disease in Indigenous communities in the Southwest US. Our study underscores the importance of integrating genomic surveillance with epidemiologic data to inform prevention strategies.