Jane Barnett
Research Mentor(s): Michal Olszewski
Mentor Department: Internal Medicine, Pulmonary and Critical Care Division/Microbiology & Immunology
Authors:
Session: Session 5 (2:00pm – 2:50pm)
Presentation Type: Poster 83
Abstract
Cryptococcus neoformans (C. neo), an opportunistic fungal pathogen, was recently ranked as critically important by the World Health Organization, with limited therapeutic options. Trehalose-6-phosphate synthase (TPS1), the first step in the trehalose sugar biosynthetic pathway, is a virulence factor for C.neo, and a potential drug target. While in contrast to the wild type (WT) strain the clearance of tps1Δ fungi in a mouse model no longer requires T cells. However, it is unknown if tps1Δ can generate T-cell memory. Therefore, we studied if exposure to tps1Δ C. neo modifies T cell responses. To test this, we intranasally exposed mice to tps1Δ C. neo, 28 days and 14 days prior to the challenge with WT C. neo (H99). We found there was no difference in CD4+ or CD8+ T cell numbers in the lungs between PBS-exposed (negative control) and tps1Δ-exposed mice. However, tps1Δ-exposure significantly improved the protective Th1/Th17 polarization of both CD4+ and CD8+ T-cells in the lungs. Further, a reduced dissemination, significantly lower fungal burdens in the brains and spleens were observed in in tps1Δ-exposed mice and their survival significantly increased. Thus, interference with cryptococcal tps1 not only facilitates fungal clearance but also improves immunogenicity of the of the fungus, suggesting that tps1-targeting therapies could provide additional protective mechanisms beyond simply inhibiting the fungus.
