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 leading fungal pathogen that can cause both mucosal and invasive infections. Invasive Candida infections cause over 10,000 deaths per year in the USA, and over 400,000 deaths per year worldwide. 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. Our long-term objective is to define the regulatory pathways and signals that promote biofilm formation, and to understand the steps in biofilm development that they control.
A second major goal is to understand the regulatory signals and pathways that are active during infection. We are the first group to conduct 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. Interestingly, while virulence is often viewed as a complex multifactorial property, our initial analysis suggests than diverse genetic pathways may feed into just a few key determinants of virulence. Our long-term objective is to determine how regulatory pathways are rewired during infection, and what the ultimate outputs may be that permit growth in the infection environment.
|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
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Supplemental Data S2.avi
Reflections on thesis advisor Boris Magasanik
Ichikawa Y, Morohashi N, Tomita N, Mitchell AP, Kurumizaka H, Shimizu M. Sequence-directed nucleosome-depletion is sufficient to activate transcription from a yeast core promoter in vivo. Biochem Biophys Res Commun. 2016 May 18.
Mitchell AP. Microbiology: Fungus produces a toxic surprise. Nature (2016). 2016 Mar 30.
Xu W, Solis NV, Filler SG, Mitchell AP. Gene Expression Profiling of Infecting Microbes Using a Digital Bar-coding Platform. J Vis Exp. 2016 Jan 13;(107).
Mitchell AP. The New Shape of EC. Eukaryot Cell. 2015 Dec;14(12):1151-2.
Xu W, Solis NV, Filler SG, Mitchell AP. Pathogen Gene Expression Profiling During Infection Using a Nanostring nCounter Platform. Methods Mol Biol. 2016;1361:57-65.
Desai JV, Cheng S, Ying T, Nguyen MH, Clancy CJ, Lanni F, Mitchell AP. Coordination of Candida albicans Invasion and Infection Functions by Phosphoglycerol Phosphatase Rhr2. Pathogens. 2015 Jul 24;4(3):573-589.
Desai JV, Mitchell AP. Candida albicans Biofilm Development and Its Genetic Control. Microbiol Spectr. 2015 Jun;3(3).
Huppler AR, Whibley N, Woolford CA, Childs EE, He J, Biswas PS, McGeachy MJ, Mitchell AP, Gaffen SL. A Candida albicans strain expressing mammalian IL-17A results in early control of fungal growth during disseminated infection. Infect Immun. 2015 Jul 6.
Liu Y, Shetty AC, Schwartz JA, Bradford LL, Xu W, Phan QT, Kumari P, Mahurkar A, Mitchell AP, Ravel J, Fraser CM, Filler SG, Bruno VM. New signaling pathways govern the host response to C. albicans infection in various niches. Genome Res. 2015 Apr 9.
Mitchell KF, Zarnowski R, Sanchez H, Edward JA, Reinicke E1, Nett JE, Mitchell AP, Andes DR. Community participation in biofilm matrix assembly and function. Proc Natl Acad Sci U S A. 2015 Mar 13.
González LM, Ruder WC, Mitchell AP, Messner WC, LeDuc PR. Sudden motility reversal indicates sensing of magnetic field gradients in Magnetospirillum magneticum AMB-1 strain. ISME J. 2014 Dec 5.
Xu W, Solis NV, Ehrlich RL, Woolford CA, Filler SG, Mitchell AP. Activation and Alliance of Regulatory Pathways in C. albicans during Mammalian Infection. PLoS Biol. 2015 Feb 18;13(2):e1002076.
Pongpom M, Liu H, Xu W, Snarr BD, Sheppard DC, Mitchell AP, Filler SG. Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during Growth in vitro versus Invasive Disease. Infect Immun. 2014 Dec 22. pii: IAI.02685-14.
Casadevall A, Mitchell, AP, Berman J,Kwon-Chung KJ, Perfect, Heitman J. Human Fungal Pathogens. Book Series: A Cold Spring Harbor Perspectives in Medicine Collection. 2014.
Desai JV, Mitchell AP, Andes DR. Fungal Biofilms, Drug Resistance, and Recurrent Infection. Cold Spring Harb Perspect Med. 2014 Oct 1;4(10).
Blankenship JR, Cheng S, Woolford CA, Xu W, Johnson TM, Rogers PD, Fanning S, Nguyen MH, Clancy CJ, Mitchell AP. Mutational analysis of essential septins reveals a role for septin-mediated signaling in filamentation. Eukaryot Cell. 2014 Sep 12.
Vasicek EM, Berkow EL, Bruno VM, Mitchell AP, Wiederhold NP, Barker KS, Rogers PD. Disruption of the Transcriptional Regulator Cas5 Results in Enhanced Killing of Candida albicans by Fluconazole. Antimicrob Agents Chemother. 2014 Sep 2.
Zarnowski R, Westler WM, Lacmbouh GA, Marita JM, Bothe JR, Bernhardt J, Lounes-Hadj Sahraoui A, Fontaine J, Sanchez H, Hatfield RD, Ntambi JM, Nett JE, Mitchell AP, Andes DR. Novel entries in a fungal biofilm matrix encyclopedia. MBio. 2014 Aug 5;5(4). pii: e01333-14.
O'Meara, T.R., Xu, W., Selvig, K.M., O'Meara, M.J., Mitchell, A.P., and Alspaugh, J.A. (2014). The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host. Mol Cell Biol 34, 673-684.
Liu, Y., Solis, N.V., Heilmann, C.J., Phan, Q.T., Mitchell, A.P., Klis, F.M., and Filler, S.G. (2014). Role of retrograde trafficking in stress response, host cell interactions, and virulence of Candida albicans. Eukaryot Cell 13, 279-287.
Raman, S.B., Nguyen, M.H., Cheng, S., Badrane, H., Iczkowski, K.A., Wegener, M., Gaffen, S.L., Mitchell, A.P., and Clancy, C.J. (2013). A competitive infection model of hematogenously disseminated candidiasis in mice redefines the role of Candida albicans IRS4 in pathogenesis. Infect Immun 81, 1430-1438.
Jung, S.I., Finkel, J.S., Solis, N.V., Chaili, S., Mitchell, A.P., Yeaman, M.R., and Filler, S.G. (2013). Bcr1 functions downstream of Ssd1 to mediate antimicrobial peptide resistance in Candida albicans. Eukaryot Cell 12, 411-419.
Desai, J.V., Bruno, V.M., Ganguly, S., Stamper, R.J., Mitchell, K.F., Solis, N., Hill, E.M., Xu, W., Filler, S.G., Andes, D.R., et al. (2013). Regulatory role of glycerol in Candida albicans biofilm formation. MBio 4, e00637-00612.
Bishop, A.C., Ganguly, S., Solis, N.V., Cooley, B.M., Jensen-Seaman, M.I., Filler, S.G., Mitchell, A.P., and Patton-Vogt, J. (2013). Glycerophosphocholine Utilization by Candida albicans: ROLE OF THE Git3 TRANSPORTER IN VIRULENCE. J Biol Chem 288, 33939-33952.
Taff, H.T., Nett, J.E., Zarnowski, R., Ross, K.M., Sanchez, H., Cain, M.T., Hamaker, J., Mitchell, A.P., and Andes, D.R. (2012). A Candida Biofilm-Induced Pathway for Matrix Glucan Delivery: Implications for Drug Resistance. PLoS Pathog 8, e1002848.
Subramanian, S., Woolford, C.A., Desai, J.V., Lanni, F., and Mitchell, A.P. (2012). Cis- and trans-acting localization determinants of pH response regulator Rim13 in Saccharomyces cerevisiae. Eukaryot Cell 11, 1201-1209.
Finkel, J.S., Xu, W., Huang, D., Hill, E.M., Desai, J.V., Woolford, C.A., Nett, J.E., Taff, H., Norice, C.T., Andes, D.R., et al. (2012). Portrait of Candida albicans Adherence Regulators. PLoS Pathog 8, e1002525.
Fanning, S., Xu, W., Solis, N., Woolford, C.A., Filler, S.G., and Mitchell, A.P. (2012). Divergent targets of Candida albicans biofilm regulator Bcr1 in vitro and in vivo. Eukaryot Cell 11, 896-904.
Fanning, S., Xu, W., Beaurepaire, C., Suhan, J.P., Nantel, A., and Mitchell, A.P. (2012). Functional control of the Candida albicans cell wall by catalytic protein kinase A subunit Tpk1. Mol Microbiol 86, 284-302.
Fanning, S., and Mitchell, A.P. (2012). Fungal biofilms. PLoS Pathog 8, e1002585.
Ganguly, S., Bishop, A.C., Xu, W., Ghosh, S., Nickerson, K.W., Lanni, F., Patton-Vogt, J., and Mitchell, A.P. (2011). Zap1 control of cell-cell signaling in Candida albicans biofilms. Eukaryot Cell 10, 1448-1454.
Finkel, J.S., Yudanin, N., Nett, J.E., Andes, D.R., and Mitchell, A.P. (2011). Application of the systematic "DAmP" approach to create a partially defective C. albicans mutant. Fungal Genet Biol 48, 1056-1061.
Finkel, J.S., and Mitchell, A.P. (2011). Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9, 109-118.
Dwivedi, P., Thompson, A., Xie, Z., Kashleva, H., Ganguly, S., Mitchell, A.P., and Dongari-Bagtzoglou, A. (2011). Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion. PLoS One 6, e16218.
Boysen, J.H., Subramanian, S., and Mitchell, A.P. (2010). Intervention of Bro1 in pH-responsive Rim20 localization in Saccharomyces cerevisiae. Eukaryot Cell 9, 532-538.
Blankenship, J.R., Fanning, S., Hamaker, J.J., and Mitchell, A.P. (2010). An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog 6, e1000752.
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