Molecular mechanisms by which S. aureus alpha-toxin impairs the antigen-specific T cell response

Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity, mortality, and economic loss. Recurrence of infection is common, highlighting the fact that S. aureus subverts the development of protective immunity. The development of a vaccine to prevent S. aureus infection has been a premier goal in the field for over two decades, yet multiple human vaccine candidates have failed in clinical trials. Population-level immunity to S. aureus disease will require targeting a virulence factor that is highly conserved across S. aureus strains, has a known mechanism of cellular and molecular action in the host, and for which naturally occurring immunity to the factor is a correlate of human protection against disease. Extensive research, including our own studies, supports the targeting of -toxin (Hla) as a virulence factor and a potential vaccine target. We have successfully leveraged human clinical studies of S. aureus-infected children and experimental perturbation of S. aureus in a mouse model system to examine the immunologic correlates of recurrent infection. While murine studies are often faulted for their lack of congruence with human immunity, our observations provide highly complementary data pointing to a critical role for S. aureus Hla in modulation of protective immunity. These data are three-fold: 1) children with increased serum antibody titers to Hla exhibit long-term protection against infection; 2) blockade of Hla in the context of experimental skin infection provides protection against the clinical manifestations of recurrent infection; and 3) Hla blunts the generation of antigen- specific T cells in experimental skin infection in mice. In spite of this knowledge, substantial limitations in our understanding of the molecular mechanisms by which Hla impairs T cell-mediated adaptive immunity remain a fundamental impediment to progress in the field. In this project, we propose to leverage well-characterized mouse models of disease and a unique human biorepository to examine how Hla interacts with the CD4+ T cell compartment, focusing specifically on the context of skin infection. Our studies will analyze the role of antigen trafficking in T cell exposure to Hla, probe T cell receptor-mediated signal transduction events during infection, and evaluate whether T cell ADAM10 expression predicts susceptibility to disease. Capitalizing on extensive genetic resources for analysis of the cell type-specific response to Hla, we will conduct a series of studies that span in vivo pathogenesis, detailed cellular immunophenotyping, and functional analysis of the mechanism by which Hla modulates antigen presentation, T cell biology, and the diversity of the adaptive immune response. These studies will provide an integrated approach to understanding how Hla imparts susceptibility to S. aureus infection, which will in turn enhance the strategic development of interventions to prevent disease. Project Number: 1R01AI196089-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Juliane Bubeck Wardenburg | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $664,076 | Activity Code: R01 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19608901