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A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Vaccine protection of leukopenic mice against Staphylococcus aureus bloodstream infection
Sabine Rauch1, Portia Gough1, Hwan Keun Kim1
1Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
Abstract:
The risk for Staphylococcus aureus bloodstream infection (BSI) is increased in immunocompromised individuals, including patients with hematologic malignancy and/or chemotherapy. Due to the emergence of antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), staphylococcal BSI in cancer patients is associated with high mortality; however, neither a protective vaccine nor pathogen-specific immunotherapy is currently available. Here, we modeled staphylococcal BSI in leukopenic CD-1 mice that had been treated with cyclophosphamide, a drug for leukemia and lymphoma patients. Cyclophosphamide-treated mice were highly sensitive to S. aureus BSI and developed infectious lesions lacking immune cell infiltrates. Virulence factors of S. aureus that are key for disease establishment in immunocompetent hosts-α-hemolysin (Hla), iron-regulated surface determinants (IsdA and IsdB), coagulase (Coa), and von Willebrand factor binding protein (vWbp)-are dispensable for the pathogenesis of BSI in leukopenic mice. In contrast, sortase A mutants, which cannot assemble surface proteins, display delayed time to death and increased survival in this model. A vaccine with four surface antigens (ClfA, FnBPB, SdrD, and SpAKKAA), which was identified by genetic vaccinology using sortase A mutants, raised antigen-specific immune responses that protected leukopenic mice against staphylococcal BSI.
Insights
A novel vaccine targeting Staphylococcus aureus surface antigens protected immunocompromised mice against bloodstream infections. This breakthrough offers hope for preventing severe infections in cancer patients and other vulnerable populations.
Area of Science:
- Immunology
- Infectious Diseases
- Vaccinology
Background:
- Immunocompromised individuals, particularly those with hematologic malignancy or undergoing chemotherapy, face increased risk of Staphylococcus aureus bloodstream infections (BSI).
- Emergence of antibiotic-resistant strains like methicillin-resistant S. aureus (MRSA) exacerbates mortality in these patients, with no current vaccine or immunotherapy available.
- Staphylococcal BSI in cancer patients carries a high mortality rate, highlighting the urgent need for effective preventative strategies.
Purpose of the Study:
- To develop and evaluate a novel vaccine strategy against Staphylococcus aureus bloodstream infections (BSI) in an immunocompromised host model.
- To identify key virulence factors of S. aureus in leukopenic mice and assess their dispensability in pathogenesis.
- To investigate the protective efficacy of a vaccine targeting specific surface antigens in preventing staphylococcal BSI.
Main Methods:
- Leukopenic CD-1 mice treated with cyclophosphamide were used to model Staphylococcus aureus BSI.
- Virulence factors of S. aureus, including alpha-hemolysin and surface determinants, were assessed for their role in pathogenesis.
- Sortase A mutants and a vaccine targeting four surface antigens (ClfA, FnBPB, SdrD, and SpAKKAA) were utilized to evaluate immune responses and protection.
Main Results:
- Cyclophosphamide-induced leukopenic mice were highly susceptible to S. aureus BSI, exhibiting lesions lacking immune cell infiltrates.
- Key S. aureus virulence factors (Hla, IsdA, IsdB, Coa, vWbp) were dispensable for pathogenesis in this leukopenic model.
- Sortase A mutants showed increased survival, and a vaccine targeting four surface antigens induced protective immune responses against staphylococcal BSI in leukopenic mice.
Conclusions:
- A vaccine strategy based on genetic vaccinology targeting specific S. aureus surface antigens can provide protection against BSI in immunocompromised hosts.
- Sortase A-mediated surface protein assembly is crucial for S. aureus pathogenesis in leukopenic mice.
- This study presents a promising vaccine candidate for preventing staphylococcal BSI in vulnerable patient populations.
