Candida albicans gastrointestinal colonization and invasive filamentation
albicans is an opportunistic fungal pathogen that is a common commensal colonizer of the
human gastrointestinal (GI) tract, but in immunocompromised hosts can cause
life-threatening candidemia. Interestingly, Candida GI tract colonization is the main
source of C. albicans found in candidemia. Previous studies showed that long-term murine
GI tract colonization with C. albican... read mores causes a host-specific, possibly immunologic,
change that results in a GI tract environment that is more restrictive to C. albicans
cells. Further, C. albicans EFG1 was the first gene for which expression was shown to
vary in colonizing C. albicans cells depending on host immune status. A restrictive GI
tract environment is more restrictive to C. albicans cells lacking the gene EFG1 than to
wild-type C. albicans cells. We examined the transcript levels of known regulators of
EFG1 transcription and activity in C. albicans colonizing mice of different immune
status. We found differential expression of genes encoding most components that function
in the same filamentation pathway as EFG1, and genes encoding components of
histone-modifying complexes involved in EFG1 regulation. Therefore, host immune status
causes extensive changes in the transcription patterns of colonizing C. albicans. We
also demonstrated that a specific portion of the murine host immune system, CD4+ cells,
is required for the maintenance of the restrictive phenotype against colonizing efg1
null cells in long-term C. albicans-colonized mice. Therefore, we have identified
specific changes to the host immune system that either result from C. albicans
colonization of the GI tract or alter the fitness of colonizing C. albicans.
Additionally, we found that GI colonization by C. albicans dramatically increases
gastric transcript levels of murine cytokines IL-22 and IL-17, but not IL-10 or
IFN-γ. During infection C. albicans forms invasive filaments that invade the
tissue of its host. The glycosylated, integral plasma membrane protein Dfi1 is important
for invasive filamentation in a laboratory model. In this thesis, we show that Dfi1
remains an integral membrane protein despite deletion of either of its two predicted
transmembrane domains, whereas deletion of both domains results in a soluble protein.
Additionally, properly-oriented Dfi1, as indicated by N-linked glycosylation, was
observed when either transmembrane domain was deleted, but was absent when both
transmembrane domains were deleted. Finally, Dfi1 lacking the N-terminal transmembrane
domain was observed at the cell periphery, whereas the double-deletion mutant was
diffusely intracellular. Therefore, Dfi1 contains two transmembrane domains which
contribute to its biogenesis.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Molecular Microbiology.
Advisor: Carol Kumamoto.
Committee: Claire Moore, Gavin Schnitzler, and Honorine Ward.
Keyword: Microbiology.read less