S. aureus causes rampant infection worldwide and poses a significant threat to public health. With the spread of antibiotic resistance, there has been a major push to develop an effective vaccine against S. aureus. However, despite decades of effort and for unknown reasons, all S. aureus vaccines tested in clinical trials have failed. Our preliminary work in mouse models suggests that use of the right adjuvants could be the key to developing a successful vaccine. We showed that a combination of ?-glucan (derived from fungal cell walls) and stimulatory molecules from S. aureus synergize to provide robust Th17-mediated protection to S. aureus reinfection. Here, we will study mechanisms underlying immune protection stimulated by these adjuvants. We will explore the molecular mechanisms and parameters that determine the efficacy and duration of protection. We will further investigate the efficacy of the protection in a humanized mouse model of S. aureus infection. The study will provide a better fundamental understanding of how an improved protective immune response to S. aureus can be induced.

Public Health Relevance

An effective vaccine is the ultimate goal in the war against S. aureus, which in recent years has become a major public health problem due to antibiotic resistance. All vaccines tested in clinical trials thus far have failed. Our data suggest that a solution may lie in understanding the underlying basic mechanisms of adjuvant efficacy. Here we propose a mechanistic study of how and why a fungal cell wall-derived adjuvant promotes robust and long lasting protection against S. aureus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI127406-04
Application #
9920668
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lapham, Cheryl K
Project Start
2017-06-26
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Thomsen, Isaac P; Liu, George Y (2018) Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries. JCI Insight 3:
Ogawa, Chihiro; Bankoti, Rashmi; Nguyen, Truc et al. (2018) Blimp-1 Functions as a Molecular Switch to Prevent Inflammatory Activity in Foxp3+ROR?t+ Regulatory T Cells. Cell Rep 25:19-28.e5
Sanchez, Marisel; Kolar, Stacey L; Müller, Sabrina et al. (2017) O-Acetylation of Peptidoglycan Limits Helper T Cell Priming and Permits Staphylococcus aureus Reinfection. Cell Host Microbe 22:543-551.e4