Glycan-specific IgM is critical for human immunity toStaphylococcus aureus

Staphylococcus aureusis a major human pathogen but the immune factors that protect against it remain elusive. In particular, high opsonic IgG titers achieved in preclinicalS. aureusanimal immunization studies have consistently failed to translate to protection in human clinical trials. Here, we investigated the antibody responses to a conserved surface glycan, Wall Teichoic Acid (WTA). IgM and IgG antibodies specific to WTA were universally present in plasma from healthy individuals. Functionally, WTA-specific IgM outperformed IgG in opsonophagocytic killing ofS. aureusand conferred passive protection againstS. aureusinfectionin vivo. In the clinical setting, WTA-specific IgM responses, but not IgG responses, were significantly lower inS. aureusbacteremia patients compared to healthy individuals, correlated with mortality risk and showed impaired bacterial opsonization. Our findings can guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against seriousS. aureusinfection.