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Inducing Meningococcal Meningitis Serogroup C in Mice via Intracisternal Delivery
Published on: November 5, 2019
Trivalent immunization with metal-binding proteins confers protection against enterococci in a mouse infection model
Ling Ning Lam1, Angie Sedra2, Jessica Kajfasz1
1Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, United States.
Abstract:
Enterococcus faecalis is ranked among the top five bacterial pathogens responsible for catheter-associated urinary tract infections, wound infections, secondary root canal infections, and infective endocarditis. Previously, we showed that inactivation of either the manganese- and iron-binding (EfaA) or zinc-binding (AdcA and AdcAII) lipoproteins significantly reduced E. faecalis virulence. Here, we explored whether immunization using a multi-valent approach induces protective immunity against systemic enterococcal infections. We found that multi-antigen antisera raised against EfaA, AdcA, and AdcAII displayed similar capacities to initiate neutrophil-mediated opsonization, like their single-antigen counterparts. Further, these antigen-specific antibodies worked synergistically with calprotectin, a divalent host metal chelator, to inhibit the growth of E. faecalis in laboratory media as well as in human sera. Using the Galleria mellonella invertebrate model and mouse peritonitis model, we showed that passive immunization with multi-antigen antisera conferred robust protection against E. faecalis infection, while the protective effects of single antigen antisera were negligible in G. mellonella, and negligible-to-moderate in the mouse model. Lastly, active immunization with the 3-antigen (trivalent) cocktail significantly protected mice against either lethal or non-lethal E. faecalis infections, with this protection appearing to be far-reaching based on immunization results obtained with contemporary strains of E. faecalis and closely related Enterococcus faecium.
Insights
A multi-antigen vaccine targeting Enterococcus faecalis lipoproteins EfaA, AdcA, and AdcAII provides robust protection against systemic infections. This trivalent vaccine shows broad efficacy in preclinical models, offering a promising strategy against enterococcal pathogens.
Area of Science:
- Microbiology and Immunology
- Infectious Diseases
- Vaccine Development
Background:
- Enterococcus faecalis is a leading cause of nosocomial infections, including UTIs, wound infections, and endocarditis.
- Previous studies identified EfaA (manganese/iron-binding) and AdcA/AdcAII (zinc-binding) lipoproteins as critical for E. faecalis virulence.
- The potential of multi-valent immunization against systemic enterococcal infections remains largely unexplored.
Purpose of the Study:
- To investigate whether a multi-valent immunization strategy can induce protective immunity against systemic Enterococcus faecalis infections.
- To evaluate the synergistic effects of multi-antigen antibodies with host factors like calprotectin.
- To assess the efficacy of passive and active immunization with multi-antigen vaccines in preclinical models.
Main Methods:
- Generation of multi-antigen antisera against EfaA, AdcA, and AdcAII lipoproteins.
- Assessment of opsonization capacity and synergistic effects with calprotectin in vitro.
- Evaluation of passive immunization in Galleria mellonella and mouse peritonitis models.
- Assessment of active immunization with a trivalent vaccine in mice challenged with E. faecalis and E. faecium.
Main Results:
- Multi-antigen antisera mediated neutrophil opsonization similarly to single-antigen antisera.
- Antigen-specific antibodies synergized with calprotectin to inhibit E. faecalis growth in vitro and in human serum.
- Passive immunization with multi-antigen antisera provided robust protection in G. mellonella and moderate protection in mice.
- Active immunization with a trivalent vaccine significantly protected mice against lethal E. faecalis infections, including against contemporary strains and E. faecium.
Conclusions:
- A multi-valent immunization approach targeting EfaA, AdcA, and AdcAII lipoproteins is effective in inducing protective immunity against systemic Enterococcus faecalis infections.
- The trivalent vaccine demonstrates broad efficacy, protecting against both E. faecalis and E. faecium, suggesting potential for broader enterococcal infection control.
- This strategy represents a promising avenue for developing novel vaccines against challenging Gram-positive bacterial pathogens.
