Wardenburg, J. B. | bioRxiv Science

bioRxiv2026

Antibody Correlates of Resilience to Staphylococcus aureus Disease and Recurrence in Children

Staphylococcus aureus remains a major global pathogen with no licensed vaccine and high recurrent infection burden, yet correlates of protection remain undefined. In a prospective pediatric cohort, we profiled 319 children spanning non-carriers, asymptomatic carriers, those with skin and soft tissue infection (SSTI), or invasive disease. We interrogated 182,149 antibody features, generating the most comprehensive S. aureus immune profiling dataset to date. Antibody responses increased with age, marked by expansion of IgG subclasses and Fc-receptor engagement. Asymptomatic carriage was associated with functional antibody profiles targeting conserved surface antigens and select toxins. Multivariate modeling robustly distinguished clinical phenotypes and identified high-value antigens associated with disease resilience. Protection from recurrent disease converged on enhanced Fc{gamma}R binding and antibody effector function. These findings nominate key antigen targets, and highlight anti-Hla neutralizing antibodies and functional antibodies to additional surface antigens that can be recapitulated through Fc engineering, informing next-generation vaccine and monoclonal antibody strategies.

immunology↗

bioRxiv2024

LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

immunology↗