Cryptococcus gattii Evades Dendritic cell Dependent Adaptive Immunity
Date
2013-08-01
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Abstract
Cryptococcus gattii is a fungal pathogen that has recently emerged on the west coast of
North America. Despite the best possible therapy, C. gattii infections cause mortality in 8-33%
of individuals that were otherwise healthy. Yet effective mechanisms of host immunity against
C. gattii remain relatively elusive. It is evident though that adaptive immunity initiated by
dendritic cells (DC) is essential for host immunity against other fungal pathogens.
We hypothesized that an acute infection with C. gattii causes a defect in the function of
DC such that their ability to present C. gattii to T cells is impaired causing ineffective clearance
of the fungus. We found that C. gattii clinical isolates from the endemic area efficiently
associated with DC and induced sufficient activation of DC required for internalization of C.
gattii to late phagolysosomes and for anti-cryptococcal activity. However, in the presence of C.
gattii DC did not change their phenotype consistent with mature DC, did not produce TNFα or
activate MAP kinases, which are essential for DC maturation and induced suboptimal T cell
responses. These studies indicated that C. gattii evades DC maturation and suggested a
bifurcation in signalling between the essential functions of DC. In addition, exogenous addition
of TNFα in a cytokine cocktail or production of TNFα by LPS recovered DC maturation in the
presence of C. gattii suggesting that DC-based therapies may allow for more favourable
outcomes for patients.
A major virulence factor for Cryptococcus is the complex polysaccharide capsule.
Therefore, we produced an acapsular mutant of C. gattii, which stimulated DC maturation in a
TNFα and p38 MAP kinase dependent manner. In addition, we found that internalization of
acapsular C. gattii and ERK activation were not required for DC maturation. Together these
observations indicated that the polysaccharide capsule of C. gattii allowed the organism to evade
DC maturation as early as at the DC cell surface, resulting in failure to induce TNFα production
and p38 MAP kinase activation that are essential for this process.
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Keywords
Cell, Microbiology, Immunology
Citation
Huston, S. M. (2013). Cryptococcus gattii Evades Dendritic cell Dependent Adaptive Immunity (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25495