Alternate lifestyles of C. albicans: Immunosensing through Efg1p promotes either colonization or pathogenesis.
albicans is a colonizing fungus of the human gastrointestinal tract. When a host becomes
immunocompromised, C. albicans can cause significant mucosal and systemic infections.
The ability of C. albicans to switch between commensal and pathogenic growth is not well
understood. The transcription factor Efg1p regulates morphology and virulence, but the
role of Efg1p during gastr... read moreointestinal colonization had not been previously
characterized. We proposed that phenotypic heterogeneity could alter the fitness of
colonizing cells to promote either colonization or pathogenesis depending on the immune
status of the host. We showed that Efg1p demonstrated phenotypic variation and is a
major regulator of GI tract colonization. efg1- cells initially hyper-colonized the GI
tract, but were preferentially eliminated by the host immune response. EFG1 showed
differential expression and activity between cells colonizing either a healthy or
immunocompromised host. This shows that colonizing organisms have different gene
expression patterns based on the host immune status. Efg1p significantly altered the
expression of genes involved in host interactions and metabolism by colonizing cells.
Susceptibility of an efg1- strain to the immune response was influenced by the
expression of SOD5, a superoxide dismutase, suggesting that reactive oxygen species are
produced by the host during GI colonization. Altered metabolism of the efg1- mutant
enabled an increase in population density, which was dependent on both carbon source and
carnitine utilization. Efg1p negatively regulated genes involved in carnitine
utilization in the gut, and this effect may contribute to hyper-colonization.
Additionally, other regulators of EFG1 and the yeast to hyphal transition were observed
to have unique effects on the ability of C. albicans to colonize the GI tract. By
balancing the metabolic activity of C. albicans and defense against the host immune
response, EFG1 can act as a sensor of the host immune status. Production of cells with
high or low Efg1p activity within a population through phenotypic variation of EFG1
expression would allow C. albicans to quickly adapt to changes in the host immune system
promoting either colonization or
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Molecular Microbiology.
Advisor: Carol Kumamoto.
Committee: Ralph Isberg, Linden Hu, Joan Mecsas, and Eleftherios Mylonakis.
Keyword: Microbiology.read less