Control of Candida albicans Filamentous Growth and Virulence

Project: Research project

Project Details

Description

Candida albicans is the major human fungal pathogen responsible for a wide variety of systemic and
mucosal infections. Immunocompromised individuals such as AIDS patients, organ transplant
recipients, cancer patients undergoing chemotherapy and recipients of artificial joints and prosthetic
devices are particularly susceptible to C. albicans infections. C. albicans is known to undergo a
morphological transition from blastospores (single round budding yeast cells) to pseudohyphal and
hyphal filaments (elongated cells attached end-to-end). The ability to undergo this transition is
required for virulence. Our long-term goal is to determine the mechanisms by which C. albicans
controls morphology and virulence in response to specific host environmental cues. In order to
achieve this goal we have identified several key transcriptional regulators that control C. albicans
filamentation as well as expression of the C. albicans filamentous growth program. We have recently
shown that expression levels of one of these regulators, UME6 (encoding a novel filament-specific
protein), are sufficient to determine C. albicans morphological form, drive hyphal filament extension
and confer enhanced virulence in a mouse model of systemic candidiasis;extension of hyphal
filaments is known to play a key role in a variety of virulence-related processes. A second regulator,
Nrg1, functions as a key repressor of filamentation and is down-regulated in response to serum and
37 C (one of the strongest filament-inducing conditions). Several lines of evidence suggest that Nrg1
and Ume6 function together to control filamentous growth and virulence in response to a variety of
specific host environmetal cues and signals. In order to address this hypothesis we will carry out the
following specific aims: 1) determine the mechanism by which Nrg1 and Ume6 control filamentous
growth as well as expression of the C. albicans filamentous growth program, 2) determine the extent
to which Nrg1 and Ume6 play a role in a variety of regulatory and signaling pathways known to be
important for C. albicans filamentous growth and virulence, 3) determine how specific host
environmental cues control the transcriptional activity of Nrg1 and Ume6 both in vitro as well as in a
mouse model of systemic candidiasis in vivo. A variety of genetic, molecular, biochemical and
genomic approaches will be taken to achieve these aims. Because the ability of C. albicans to
undergo a morphological conversion is required for virulence, these studies will also significantly
improve our understanding of the underlying mechanisms of fungal pathogenesis and eventually
lead to the development of more effective antifungal therapies
StatusFinished
Effective start/end date9/30/098/31/11

Funding

  • National Institutes of Health: $297,000.00

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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