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

Award Number: R01AI196089
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $664,076 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	4/1/2026	NEW	$664,076
														Subtotal = $664,076

Grand Total All Awards = $664,076

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

Award Number: R01AI196089

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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