Abstract
Staphylococcus aureus is a major cause of bloodstream infections, but how variation between strains in their ability to adhere to host proteins influences disease severity remains unclear. Here we show that adhesion is a highly variable and biologically important trait in 236 phylogenetically diverse, representative bacteremia isolates profiled for binding to fibrinogen and fibronectin and analysed together with bacterial whole-genome sequences and matched patients’ clinical data. Stronger fibrinogen-binding, particularly in strains lacking α-toxin, correlates with heightened systemic inflammation (r = 0.401, P = 0.0001) but lower mortality (16.6% vs. 38.7%, P = 0.018), linking bacterial adhesion to distinct clinical outcomes. Genome-wide association analyses identify top-associated variants in genes encoding known adhesins (clfA, fnbA, fnbB, ebh), other surface factors (spa, sdrH), mobile genetic elements, and novel loci (csbB, glcA), although not statistically significant. Functional analyses reveal that protein A limits ClfA-dependent fibrinogen binding through steric hindrance, CsbB interferes with ClfA exposure on bacterial surface, and GlcA enhances fibronectin binding via metabolic regulation. These findings define adhesion as a polygenic, evolutionarily variable trait and suggest that highly-adhesive, α-toxin-defective isolates promote inflammatory but self-limiting infections, whereas weakly adhesive, high-toxicity strains favour immune evasion and severe disease.
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Acknowledgements
We thank the VIRSTA Study Group as well as clinicians and microbiologists who contributed to the recruitment of patients included in the different cohorts. We thank Karolina Mijas and Maciej Rykała for their technical support in testing isolates’ hemolytic activity. We thank Prof. Timothy J. Foster for his valuable comments on the manuscript. The NTML was provided by the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) for distribution through BEI Resources, NIAID, NIH. Funding: This work was funded by the National Science Center, Poland, SONATA grant 2018/31/D/NZ6/02648 (MZ) and OPUS grant 2022/47/B/NZ6/03379 (MZ).
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Coll, F., Rożen, P., Budnik, M. et al. Genetic determinants of Staphylococcus aureus adhesion shape virulence trade-offs in bacteremia. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72657-5
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DOI: https://doi.org/10.1038/s41467-026-72657-5
