Enhanced Staphylococcus aureus protection by uncoupling of the α-toxin-ADAM10 interaction during murine neonatal vaccination

Staphylococcus aureus remains a leading global cause of bacterial infection-associated mortality and has eluded prior vaccine development efforts. S. aureus α-toxin (Hla) is an essential virulence factor in disease, impairing the T cell response to infection. The anti-Hla antibody response is a corr...

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Published in:Nature communications Vol. 15; no. 1; pp. 8702 - 14
Main Authors: Tomaszewski, Kelly L., Blanchard, Meagan, Olaniyi, Reuben, Brenton, Hannah R., Hayes, Samantha, Fatma, Farheen, Amarasinghe, Gaya K., Cho, Byoung-Kyu, Goo, Young Ah, DeDent, Andrea C., Fritz, Stephanie A., Wardenburg, Juliane Bubeck
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 08.10.2024
Nature Publishing Group
Nature Portfolio
Subjects:
13/31
14
38
59
631/250/255/1318
631/326/41/2533
631/326/590/2294
64
64/60
692/308/575
82/58
ADAM10 Protein - immunology
ADAM10 Protein - metabolism
Amyloid Precursor Protein Secretases - immunology
Amyloid Precursor Protein Secretases - metabolism
Animal models
Animals
Animals, Newborn
Antibodies, Bacterial - immunology
Antibodies, Neutralizing - immunology
Antibody response
Antitoxins
Bacterial diseases
Bacterial Toxins - immunology
Bacterial Toxins - metabolism
Female
Hemolysin Proteins - immunology
Hemolysin Proteins - metabolism
Histocompatibility antigen HLA
Humanities and Social Sciences
Humans
Immunity
Immunization
Lymphocytes
Lymphocytes T
Membrane Proteins - immunology
Membrane Proteins - metabolism
Mice
Mice, Inbred C57BL
multidisciplinary
Neonates
Neutralizing
Offspring
Science
Science (multidisciplinary)
Staphylococcal Infections - immunology
Staphylococcal Infections - prevention & control
Staphylococcal Vaccines - administration & dosage
Staphylococcal Vaccines - immunology
Staphylococcus aureus
Staphylococcus aureus - immunology
Staphylococcus infections
Toxins
Vaccination
Vaccine development
Vaccines
Virulence factors
α-Toxin
ISSN:2041-1723, 2041-1723
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Summary:Staphylococcus aureus remains a leading global cause of bacterial infection-associated mortality and has eluded prior vaccine development efforts. S. aureus α-toxin (Hla) is an essential virulence factor in disease, impairing the T cell response to infection. The anti-Hla antibody response is a correlate of human protective immunity. Here we observe that this response is limited early in human life and design a vaccine strategy to elicit immune protection against Hla in a neonatal mice. By targeted disruption of the interaction of Hla with its receptor ADAM10, we identify a vaccine antigen (Hla H 35L/ R 66C/ E 70C , Hla HRE ) that elicits an ~100-fold increase in the neutralizing anti-Hla response. Immunization with Hla HRE enhances the T follicular helper (T FH ) cell response to S. aureus infection, correlating with the magnitude of the neutralizing anti-toxin response and disease protection. Furthermore, maternal Hla HRE immunization confers protection to offspring. Together, these findings illuminate a path for S. aureus vaccine development at the maternal-infant interface. Staphylococcus aureus infection results in robust induction of immunity but the development of efficacious vaccines remains challenging. Here the authors present a vaccine that amplifies T cell immunity early in life by targeting the S. aureus α-toxin-ADAM10 interaction in a murine model.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-52714-7