Aaron P. Mitchell
200B Mellon Institute
Department of Biological Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Ph.D., Massachusetts Institute of Technology
Postdoctoral Appointment, Department of Biochemistry and Biophysics, University of California at San Francisco
How does a pathogen cause infection? That is the question that drives our research. Our studies focus on Candida albicans, a major fungal pathogen that can cause both mucosal and invasive infections. Invasive Candida infections cause over 10,000 deaths per year in the USA. Our overall objectives are to define the determinants of pathogenicity and drug responses in order to identify strategies to improve diagnosis and therapeutics.
One major goal is to understand biofilm formation. Biofilms are surface-associated growth forms, and biofilm cells have properties that are distinct from free-living cells. We have defined genes that govern biofilm formation through several approaches based on transcriptional regulation. First, we identified transcription factors and protein kinases that are required for biofilm formation or cell-substrate adherence, defined their target genes through expression profiling, and then used gene deletion and overexpression-based manipulations to identify functional target genes. Second, we have conducted genome-wide profiling of biofilms to identify strain-independent gene expression responses to this growth state. We have identified major surface adhesins that mediate biofilm formation, as well as regulatory pathways and small molecule signals that govern biofilm initiation and maturation.
A second major goal is to understand the regulatory signals and pathways that are active during infection. Many prior studies have focused on non-essential genes as mediators of pathogenicity; we are taking a complementary approach to define the roles of select essential genes. We have borrowed the "DAmP" approach from our colleagues who work on S. cerevisiae, and also have developed a panel of weak promoter replacement cassettes, in order to manipulate essential genes. We have also conducted gene expression profiling during infection through use of extremely sensitive nanoString technology. This work has allowed us to define regulatory pathways active during infection, which are in many ways distinct from those defined previously during growth in vitro.
|Gene expression changes associated with adherence-defective mutants (Finkel et al., 2012).||Confocal images of biofilms produced by wild-type, mutant, and complemented strains. The mutation lies in a gene that is highly induced during biofilm growth (Desai et al., submitted).||Scanning electron micrograph of a biofilm that presents tubular hyphal cells and amorphous extracellular matrix material (Fanning and Mitchell, 2012).|
Fanning et al 2012 Mol Micro Microarray Data GSE38846.xls
All TIGR sequences 08_15_05-fa part1.doc
All TIGR sequences 08_15_05-fa part2.doc
All TIGR sequences 08_15_05-fa part3.doc
All TIGR sequences 08_15_05-fa part4.doc
All TIGR sequences 08_15_05-fa part5.doc
Supplemental Data S2.avi
Desai JV, Bruno VM, Ganguly S, Stamper RJ, Mitchell KF, Solis N, Hill EM, Xu W, Filler SG, Andes DR, Fanning S, Lanni F, Mitchell AP. Regulatory Role of Glycerol in Candida albicans Biofilm Formation. MBio. 2013 Apr 9;4(2). pii: e00637-12. doi: 10.1128/mBio.00637-12. (Full Text)
Raman SB, Nguyen MH, Cheng S, Badrane H, Iczkowski KA, Wegener M, Gaffen SL, Mitchell AP, Clancy CJ. A competitive infection model of hematogenously disseminated candidiasis in mice redefines the role of Candida albicans IRS4 in pathogenesis. Infect Immun. 2013 Feb 19.
Fanning S, Xu W, Beaurepaire C, Suhan JP, Nantel A, Mitchell AP. Functional control of the Candida albicans cell wall by catalytic protein kinase A subunit Tpk1. Molecular microbiology 86:284-302, 2012.
Taff HT, Nett JE, Zarnowski R, Ross KM, Sanchez H, Cain MT, Hamaker J, Mitchell AP, Andes DR. A Candida Biofilm-Induced Pathway for Matrix Glucan Delivery: Implications for Drug Resistance. PLoS Pathog 8:e1002848, 2012.
Subramanian S, Woolford CA, Desai JV, Lanni F, Mitchell AP. Cis- and trans-acting localization determinants of pH response regulator Rim13 in Saccharomyces cerevisiae. Eukaryot Cell 11:1201-1209, 2012.
Badrane H, Nguyen MH, Blankenship JR, Cheng S, Hao B, Mitchell AP, Clancy CJ. Rapid redistribution of phosphatidylinositol-(4,5)-bisphosphate and septins during the Candida albicans response to caspofungin. Antimicrob Agents Chemother 56:4614-4624, 2012.
Fanning S, Xu W, Solis N, Woolford CA, Filler SG, Mitchell AP. Divergent targets of Candida albicans biofilm regulator Bcr1 in vitro and in vivo. Eukaryot Cell 11:896-904, 2012.
Xu W and Mitchell AP. Fungal morphogenesis: in hot pursuit. Curr Biol 22:R225-227, 2012.
Fanning S and Mitchell AP. Fungal biofilms. PLoS Pathog 8:e1002585, 2012.
Finkel JS, Xu W, Huang D, Hill EM, Desai JV, Woolford CA, Nett JE, Taff H, Norice CT, Andes DR, Lanni F, Mitchell AP. Portrait of Candida albicans Adherence Regulators. PLoS Pathog 8:e1002525, 2012.
Ganguly S, Bishop AC, Xu W, Ghosh S, Nickerson KW, Lanni F, Patton-Vogt J, Mitchell AP. Zap1 control of cell-cell signaling in Candida albicans biofilms. Eukaryot Cell 10:1448-1454, 2011.
Blankenship JR and Mitchell AP. Candida albicans Adds More Weight to Iron Regulation. Cell host & microbe 10:93-94, 2011.
Finkel JS, Yudanin N, Nett JE, Andes DR, Mitchell AP. Application of the systematic "DAmP" approach to create a partially defective C. albicans mutant. Fungal Genet Biol 48:1056-1061, 2011.
Ganguly S and Mitchell AP. Mucosal biofilms of Candida albicans. Current opinion in microbiology 14:380-385, 2011.
Finkel JS and Mitchell AP. Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9, 109-118, 2011.
Watch Dr. Mitchell discuss the research completed in his laboratory and more.