|Department Affiliations||Molecular Biology and Genetics|
|SOM Address||617 Hunterian|
Matthew Frieman 2000 – 2004
Renee Domergue Mundy 2002 – 2007
.Jonathan Trow 2003 – 2013
We are interested in how microbial pathogens have evolved to colonize and persist in the mammalian host. We study the fungal pathogen Candida glabrata, an opportunistic pathogen responsible for 15-20% of Candidiasis in the US. This organism only recently diverged from S. cerevisiae and many of the same genetic approaches available in S. cerevisiae can be applied to understand the virulence of this yeast pathogen.
We focus on two areas of investigation. First, we have generated large numbers of transposon mutants of C. glabrata and are screening these for mutants that are specifically altered in adherence to epithelial cells, in survival in the presence of macrophages and PMNs. We are also screening mutants directly in mice for those unable to colonize or persist in the normal target organs (liver, kidney and spleen). These broad screens will help identify virulence genes (genes that have evolved in response to the host environment). Second, we are concentrating on a family of genes (the EPA genes) that allow the organism to bind to host cells. The EPA genes number at least 20 and are present in the genome as clusters of genes located close to the telomeres. We have shown that a subset of them are able to mediate adherence to host epithelial cells. In genomic organization, the telomeric clustering resembles the organization of genes encoding surface proteins in a number of other species and as in those other species (Plasmodium (the malaria parasite), trypanosomes and Pneumocystis) the majority of the EPA genes are transcriptionally silent. We are trying to understand the contribution of this family to virulence in C. glabrata by addressing three questions, using the genetic tools we have already put in place. What is the ligand specificity of different family members? How are the genes normally regulated during infection? What mechanisms normally act to keep the genes transcriptionally silent and how is that silencing regulated?
- Castano I, Kaur R, Pan S, Cregg R, De Las Penas R, Guo N, Biery, MC, Craig NL, Cormack BP. Tn-7-based genome�wide random insertional mutagenesis of Candida glabrata. (2003) Genome Research, in press
- Frieman MB, McCaffery JM, Cormack BP. Modular domain structure in the Candida glabrata adhesin Epa1p, a b1,6 glucan-crosslinked cell wall protein. (2002) Molecular Microbiology 46, p479-92
- Cormack, BP, Ghori, N, Falkow, S. An adhesin of the yeast pathogen Candida glabrata mediating adherence to human epithelial cells. (1999) Science 285, p578-582