Robert Wheeler, Ph.D.
AB (1993) Harvard College
PhD (2000) Stanford University
Post-doctoral: Whitehead Institute
Fungal host-pathogen interaction
There is an ongoing war between microbial pathogens and their hosts.For each mode of host immunity, the challenger has designed a defense, which in turn leads the host to devise a new avenue of attack. Opportunistic pathogens such as the fungus Candida, a leading cause of hospital-acquired infection and an increasingly important killer, must be able to constantly evade the attacks of the host and exploit any break in host defense caused by a compromise of immunity. The host, in turn, depends to a large part on innate immune responses to protect itself against this fungus. Using high throughput cell biology and genetics, we are elucidating this ongoing battle between fungi and host from both sides of the conflict.
Our work attacks fundamental biological questions that have clinical relevance. In the near term, we expect to understand the normal host-pathogen interaction in disease and during drug treatment. In the long term, we expect to identify new means to prevent and treat fungal infection through attacking the fungus and modulating immune response.
Microbial strategies for resisting immune attack
Candida is recognized by the innate arm of the immune system through evolutionarily conserved fungal surface molecules. Although innate immune cells can recognize several different surface molecules, the fungus can cover some molecules to tailor the immune response.
The sugar β-glucan is present throughout the cell wall of Candida, but as we discovered, the pathogen masks β-glucan from immune recognition to mute immune response. We discovered that a potent antifungal drug has an unexpected side-effect and can cause increased exposure of β-glucan in addition to killing fungi.We are devising and exploiting novel methodology to look at the clinical consequences of treating fungal infection with this antifungal drug.
We have recently begun using a transparent zebrafish model to probe host-pathogen interactions (Brothers et al. 2011, Tobin et al. 2012, Gratacap et al. 2013, Brothers et al. 2013). This model permits the real-time visualization of innate immune attack. Using this model, we have found that Candida-innate immune interactions differ in vivo from our expectations based on in vitro experiments. We are currently using this model to probe the cellular effects of loss of phagocyte NADPH oxidase function. In the future, this model holds promise for understanding the molecular mechanisms that regulate Candida interaction with innate immune cells, endothelial cells and epithelial cells.
Publications (current as of August 2016)
- Mallick E.M., Bergeron A., Jones Jr S.K.., Newman Z.R., Brothers K.M., Creton R., Wheeler R.T., and Bennett R.J. (2016) Phenotypic plasticity regulates Candida albicans interactions and virulence in the vertebrate host. Front. Microbiol. 7, 280.
- Hopke A., Nicke N., Hidu E.E., Degani G., Popolo L., and Wheeler R.T. (2016). Neutrophil Attack Triggers Extracellular Trap-Dependent Candida Cell Wall Remodeling and Altered Immune Recognition. PLoS Pathogens. May 25;12(5):e1005644.
- Leach M.D., Farrer R.A., Tan K., Miao Z., Walker L.A., Cuomo C.A., Wheeler R.T., Brown A.J.P., Wong K.H. and Cowen L.E. (2016) Global Analysis of Temperature-Dependent Control of Gene Expression, Chromatin Architecture and Virulence via Hsf1. Nat Commun. 2016 May 26;7:11704.
- Moyes D.L., Wilson D., Richardson J.P., Mogavero S., Tang S.X., Wernecke J., Höfs S., Gratacap R.L., Robbins J., Runglall M., Murciano C., Blagojevic M., Thavaraj S., Förster T.M., Hebecker B., Kasper L., Vizcay G., Iancu S.I., Kichik N., Häder A., Kurzai O., Luo T., Krüger T., Kniemeyer O., Cota E., Bader O., Wheeler R.T., Gutsmann T., Hube B. and Naglik J.R. (2016). Candidalysin: A fungal peptide toxin critical for mucosal infection. Nature. Mar 30. doi: 10.1038/nature17625.
- Voelz, K., Gratacap R.L., Wheeler R.T. (2015). A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides. Dis. Model. Mech. Nov;8(11):1375-88.
- Gratacap R.L., Bergeron A.C., Wheeler R.T. (2014). Modeling mucosal candidiasis in larval zebrafish by swimbladder injection. J. Vis. Exp. Issue 93: e52182.
- Gilbert A.S., Wheeler R.T., May R.C. (2014) Fungal Pathogens: Survival and Replication within Macrophages. Cold Spring Harb Perspect Med. 2014 Nov 10;5(7):a019661.
- Davis S.E., Hopke, A., Minkin, S.C. Jr., Montedonico, A.E., Wheeler, R.T., Reynolds, T.B. (2014). Masking of β(1-3)-glucan in the cell wall of Candida albicans from detection by innate immune cells depends on phosphatidylserine. Infect. Immun. 82(10):4405-13.
- Hogan, D.A., Wheeler, R.T. (2014). The complex roles of NADPH oxidases in fungal infection. Cell. Microbiol. 16(8):1156-1167.
- Gratacap RL^, Wheeler RT (2014) Exploitation of zebrafish to enable intravital study of eukaryotic pathogen-host interactions. Dev. Comp. Immunol. 46(1):108-115. Feb 1. pii: S0145-305X(14)00021-4.
- Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, Masedunskas A, Weigert R, Mikelis C, Wan W, Lee CR, Lim JK, Yang JC, Laird GM, Wheeler RT, Alexander BD, Perfect JR, Gao J-L, Kullberg B-J, Netea MG, and Murphy PM (2013) Chemokine Receptor CX3CR1 Promotes Early Fungal Clearance and Survival in Systemic Candidiasis by Inhibiting Apoptosis of Kidney Resident Macrophages J. Clin. Invest. Dec 2;123(12):5035-51.
- Brothers KM**, Gratacap RL^, Barker SE^, Newman ZR**, Norum A*, Wheeler RT (2013) NADPH oxidase-driven phagocyte chemotaxis controls Candida albicans filamentous growth and prevents mortality. PLoS Pathog. 9(10):e1003634.
- Gratacap RL^, Rawls JF, Wheeler RT (2013) Mucosal candidiasis elicits activation of NF-κB, proinflammatory gene expression and localized neutrophilia in a transparent vertebrate mini-host. Disease Models & Mechanisms. Jul 4
- Marakalala MJ, Vautier S, Potrykus J, Walker LA, Shepardson KM, Hopke A**, Mora-Montes HM, Kerrigan A, Netea MG, Murray GI, MacCallum DM, Wheeler RT, Munro CA, Gow NAR, Cramer RA, Brown AJP and Brown GD (2013) Differential adaptation of Candida albicans in vivo modulates immune recognition by Dectin-1. PLoS Pathogens. 9(4): e1003315.
- Jiménez-López C, Collette JR, Brothers KM*, Shepardson KM, Cramer RA, Wheeler RT, Lorenz MC (2013) Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species. Eukaryot. Cell. 2013; 12(1): p. 91-100
- Brothers, KM* and Wheeler, RT (2012) Non-invasive imaging of zebrafish larvae as a model of disseminated candidiasis. J Vis Exp. 30(65):pii 4051.
- Tobin, DM, May, RC, Wheeler, RT (2012) Zebrafish: a see-through host and a fluorescent toolbox to probe host-pathogen interaction. PLoS Pathog. 8(1):e1002349.
- Brothers K.M.*, Newman Z.R.*, Wheeler R.T. (2011) Live imaging of disseminated candidiasis in zebrafish reveals role of phagocyte oxidase in limiting filamentous growth. Eukaryot Cell. 2011 Jul; 10(7):932-44 Epub 2011 May 6. PMID: 21551247
- Moxley J.F., Jewett M.C., Antoniewicz M.R., Villas-Boas S.G., Alper H., Wheeler R.T., Tong L., Hinnebusch A.G., Ideker T., Nielsen J., Stephanopoulos G. (2009) Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6477-82.
- Johnnidis J.B., Harris M.H., Wheeler R.T., Stehling-Sun S., Lam M.H., Kirak O., Brummelkamp T.R., Fleming M.D. and Camargo F.D. (2008) Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. Feb 28; 51(7182):1125-9.
- Wheeler R.T., Kombe D., Agarwala, S. and Fink G.R. (2008) Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment. PLoS Pathog. 2008 Dec;4(12):e1000227. Epub 2008 Dec 5. PMID:19057660.
- Wheeler R.T., Fink G.R. (2006) A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. Apr;2(4):e35. Epub 2006 Apr 28.
- Wheeler, R. T., Kupiec, M., Magnelli, P., Abeijon, C. and Fink, G.R. (2003) A Saccharomyces cerevisiae mutant with increased virulence. Proc Natl Acad Sci U S A. 100(5):2766-70.
- Wheeler, R. T. and Shapiro, L. (1999) Differential localization of two histidine kinases controlling bacterial cell differentiation. Molecular Cell 4, 683-694
- Wheeler, R. T., Gober, J. W. and Shapiro, L. (1998) Protein localization during the Caulobacter crescentus cell cycle. Curr. Opin. Microbiol. 6, 636-642.
- Wheeler, R. T. and Shapiro, L. (1997) Bacterial Chromosome Segregation: Is There a Mitotic Apparatus? Cell 88, 577-579.
- Winzeler, E., Wheeler, R. and Shapiro, L. (1997) Transcriptional analysis of the Caulobacter 4.5S RNA ffs gene and the physiological basis of an ffs mutant with a Ts phenotype. J. Mol. Biol. 272(5), 665-676.
Current and Recently Completed Grant Support (current as of August 2016)
- Burroughs Wellcome Fund (Investigators in the Pathogenesis of Infectious Disease); (PI: Wheeler); Term: 7/2014-6/2019; Title: “Phagocytes block fungal dimorphism to defend the epithelial barrier”
- Merck & Co., Inc. (PI: Wheeler); Term: 6/2013-9/2014
- MAFES/USDA Hatch (PI: Wheeler); Term: 10/2012-9/2017; Title: In vivo innate immune response to fungal infection
- NIH/NIAID R15 (PI: Wheeler); Term: 3/2012-2/2015; Title: Genetics and visualization of innate host response to C. albicans infection in vivo
- Regeneron Pharmaceuticals, Inc. (PI: Wheeler); Term: 9/2012-3/2015