Coordinated Regulation of Virulence Genes in C. neoformans

Research project

Description

Project Summary. To survive within the hostile environment of the infected host, pathogenic
microorganisms must be able to sense and adapt to changing environmental conditions. This
adaptation requires a coordinated regulation of multiple factors for growth and survival. Like many
infectious agents, the human fungal pathogen Cryptococcus neoformans uses the conserved
signaling molecule cyclic AMP (cAMP) to regulate its response to external stresses. The central
components of cAMP signal transduction pathways are highly conserved among microorganisms.
However, the main hypothesis of this proposal is that the upstream activating signals and the
downstream effectors of cAMP are functionally specialized in microbial pathogens. This
specialization allows pathogenic organisms to use cAMP signaling to control their virulence
potential. Increased cAMP production activates a series of protein interactions that allows C.
neoformans to adapt to the host environment. Specifically, the C. neoformans cAMP pathway
regulates the induction of capsule and melanin, two cellular factors required for pathogenesis. This
regulation occurs at the level of transcription. Therefore, the experiments of this proposal will
identify trans- and cis-acting regulatory elements that mediate the effect of cAMP on the
transcription of capsule-associated genes. Moreover, defining the regulatory networks controlled
by cAMP-dependent transcription factors will allow us to explore broad issues in environmental
sensing, cellular stress, and microbial virulence. Specific Aim 1 proposes bioinformatic and
transcriptional profiling approaches to identify transcription factors that control C. neoformans
capsule gene expression. Specific Aim 2 outlines detailed testing of selected transcriptional
regulators to define their role in capsule induction. Experiments in Specific Aim 3 will define the
direct and indirect target genes of the transcription factors identified in the first two Aims.
StatusActive
Effective start/end date7/1/096/30/21

Funding

  • National Institutes of Health: $451,544.00

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Virulence
Genes
Therapeutics
Cryptococcus neoformans
Immune Evasion
Infection
Fungal Capsules
Host-Pathogen Interactions
Premature Mortality
Antifungal Agents
Organ Transplantation
Computational Biology
Communicable Diseases
Immune System
Signal Transduction
Acquired Immunodeficiency Syndrome
Fungi
Transcription Factors
Growth
Pharmaceutical Preparations