Understanding Fungal Pathogenesis
A vast majority of healthy individuals are affected with a candida infection (such as a diaper rash, thrush or vaginitis) in their life-time, with half of them suffering from recurring infections. Immunocompromised individuals (transplant and AIDs patients, neonates etc) are susceptible to a blood stream infection with high mortality rates. The rate of hospital acquired candida infections is on the rise partly because therapeutic avenues of managing fungal infections are limited.
We have developed a whole animal model to understand the genetic and
molecular mechanisms of fungal pathogenesis. Using Caenorhabditis elegans as a model host, we have found that fungi (non-pathogenic S. cerevisae or the human pathogen C. albicans) infect the worm, producing visible disease phenotypes and death. Our study is unique because, first, it uses liquid cultures for the microbes as well as egg preparations for the animal host making it well suited for high-throughput whole genome analyses. Secondly, our assay allows us to evaluate genetic contributions of the fungal pathogen, via mutant libraries as well as the host, via RNA interference (RNAi)-mediated knockdown library is available for C. elegans These unique tools allow us to systematically scan the entire genomes to identify fungal virulence factors and modulators of host immunity to fully understand the pathogenic process as well as develop better antifungals.
Small molecule signalling
Fungi use chemical signals to assess whether conditions are favorable for
infection. The ability to communicate with one another allows microbes to
coordinate gene expression, thereby synchronously altering their behavior.
Therefore disrupting these signals would disrupt the infection process.
Secondary metabolites, like Indole acetic acid (IAA), are involved in both
intra- and interspecies communication mechanisms. IAA is the major Auxin (growth hormone) in plants and, since Charles Darwin's discovery over 70 years ago, has been implicated in virtually every aspect of plant growth and development. However, several organisms, including humans, produce IAA as a catabolic product of indoles, such as tryptophan and serotonin. We have demonstrated that fungi perceive, synthesize and respond to IAA. We are using genomic and genetic tools to identify components of the IAA signal transduction mechanism in fungi (S. cerevisiae and C. albicans). For example we have already identified the IAA transporters. We are investigating candidates for putative IAA receptor that would bind IAA and regulates its downstream effects by modulating gene expression. This research will greatly advance our understanding of how secondary metabolites are exploited as signaling molecules in fungi. In the long run, a basic understanding of how fungal secondary metabolites are used as signals that regulate pathogenesis could lead to design of better antifungal agents, of which few are currently known.
In collaboration with researchers at U Mass Medical we have developed assays and initiated high throughput drug screens to identify chemical inhibitors of C. albicans.
My previous study demonstrated that fungi use the plant hormone IAA as an extracellular signal to initiate the infection process. IAA is thought to be synthesized de novo at a wound site on a plant. This suggests that IAA is important in the study of plant-pathogen interaction. We have developed an assay using the model plant Nicotiana benthamiana to further study plant-fungal interactions. Furthermore, we have discovered that fungi have multiple pathways for IAA synthesis. We hope to identify the genes for IAA synthesis in yeast because some of these pathways have been illusive in plants. Our study would not only facilitate their identification but also parse out the role of small molecule signaling molecules in fungi and how it relates to plant pathogenesis.
S. cerevisiae is one of the best organisms for conducting controlled,
unbiased large-scale studies. The data from such studies are also available
to the scientific community
The research goal is to understand and ultimately manage fungal diseases. We use a biochemical, molecular genetic, genomic, and behavioral tools to explore fungal virulence strategies. In collaboration with researchers at UMass Medical, we have initiated high throughput chemical screens for antifungal drug discovery.