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Published on: February 14, 2011
Efficacy of Antibody to PNAG Against Keratitis Caused by Fungal Pathogens
Ge Zhao1, Tanweer S Zaidi1, Cagla Bozkurt-Guzel1
1Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
Purpose:
Developing immunotherapies for fungal eye infections is a high priority. We analyzed fungal pathogens for expression of the surface polysaccharide, poly-N-acetyl glucosamine (PNAG), and used a mouse model of ocular keratitis caused by Aspergillus flavus, A. fumigatus, or Fusarium solani to determine if PNAG was an immunotherapy target and requirements for ancillary cellular and molecular immune effectors.
Methods:
Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence was used to detect PNAG on fungal cells. Keratitis was induced by scratching corneas of C57BL/6, IL-17R KO, RAG-1 KO, or IL-22 KO mice followed by inoculation with fungal pathogens. Goat antibodies to PNAG, a PNAG-specific human IgG1 monoclonal antibody, or control antibodies were injected either prophylactically plus therapeutically or therapeutically only, and corneal pathology and fungal levels determined in infected eyes at 24 or 48 hours after infection.
Results:
All tested fungal species produced PNAG. Prophylactic or therapeutic treatment by intraperitoneal (IP) injection of antibody to PNAG combined with post-infection topical application of antibody, the latter also used for A. fumigatus, led to reduced fungal levels, corneal pathology, and cytokine expression. Topical administration only of the PNAG monoclonal antibodies (MAb) reduced fungal loads and corneal pathology. There was no antibody protection in IL-17R KO, RAG-1 KO, or IL-22 KO mice.
Conclusions:
Poly-N-acetyl glucosamine is produced by clinically important fungal ocular pathogens. Antibody to PNAG demonstrated protection against Aspergillus and Fusarium keratitis, requiring T cells producing IL-17 and IL-22. These findings indicate the potential to prevent or treat fungal infections by vaccines and immunotherapeutics to PNAG.
Insights
Antibodies targeting poly-N-acetyl glucosamine (PNAG) show promise for treating fungal eye infections. This immunotherapy requires specific T cell responses for protection against keratitis caused by Aspergillus and Fusarium.
Area of Science:
- Ophthalmology
- Immunology
- Mycology
Background:
- Fungal eye infections pose a significant threat, necessitating novel immunotherapies.
- Poly-N-acetyl glucosamine (PNAG) is a surface polysaccharide found on various fungal pathogens.
Purpose of the Study:
- To investigate PNAG as a potential immunotherapy target for fungal keratitis.
- To determine the immune effector requirements for anti-PNAG immunotherapy.
Main Methods:
- PNAG expression was analyzed on fungal pathogens using ELISA and immunofluorescence.
- A mouse model of fungal keratitis was established using Aspergillus and Fusarium species.
- Mice were treated with anti-PNAG antibodies (prophylactically and/or therapeutically) and immune-deficient models (IL-17R KO, RAG-1 KO, IL-22 KO).
Main Results:
- All tested fungal species expressed PNAG.
- Anti-PNAG antibody treatment reduced fungal burden, corneal pathology, and cytokine levels.
- Immune protection was dependent on T cells producing IL-17 and IL-22, as evidenced by lack of protection in KO mice.
Conclusions:
- PNAG is a viable target for immunotherapies against fungal ocular infections.
- Anti-PNAG antibodies demonstrate efficacy in treating keratitis caused by Aspergillus and Fusarium.
- Effective immunotherapy requires T cell-mediated immunity, specifically IL-17 and IL-22 production.
