Robert Wheeler

Education

PhD (2000) Stanford University
AB (1993) Harvard University

Biosketch

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.

Research Interests

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.

Host strategies for clearing fungal pathogens

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 thatCandida-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.
Lab Photo March 2014

Lab Photo March 2014

 

 

Selected Publications

  • Gratacap R.L., Wheeler, R.T. (2014) Exploitation of zebrafish to enable intravital study of eukaryotic pathogen-host interactions. Dev. Comp. Immunol. 46(1):108-15.
  • Hogan, D.A., Wheeler, R.T. (2014). The complex roles of NADPH oxidases in fungal infection. Cell. Microbiol. 16(8):1156-1167.
  • Davis S.E., Hopke, A., Minkin, S.C. Jr., Montedonico, A.E., Wheeler, RT, 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.
  • Gilbert, A.S., Wheeler, R.T., May, R.C. (2014) Fungal Pathogens: Survival and Replication within Macrophages. Cold Spring Harb Perspect Med. Published online Nov. 10, 2014.
  • Gratacap, R.L., Bergeron, A.C., Wheeler, R.T. (2014). Modeling mucosal candidiasis in larval zebrafish by swimbladder injection. J. Vis. Exp. Issue 93
  • Jiménez-López C., Collette J.R., Brothers K.M., Shepardson K.M., Cramer R.A., Wheeler R.T., and Lorenz M.C. (2013) Candida albicans induces arginine biosynthetic genes in response to host-derived reactive oxygen species. Euk Cell; 12(1): 91-100.
  • Marakalala M.J., Vautier S., Potrykus J., Walker L.A., Shepardson K.M., Hopke A., Mora-Montes H.M., Kerrigan A., Netea M.G., Murray G.I., MacCallum D.M., Wheeler R., Munro C.A., Gow N.A.R., Cramer R.A., Brown A.J.P. and Brown G.D. (2013) Differential adaptation of Candida albicans in vivo modulates immune recognition by Dectin-1. PLoS Pathogens. 9(4):e1003315.
  • Gratacap R.L., Rawls J.F., Wheeler R.T. (2013) Mucosal candidiasis elicits NF-κB activation, proinflammatory gene expression and localized neutrophilia in zebrafish. Dis. Model. Mech. 6(5) 1260-1270.
  • Brothers K.M., Gratacap R.L., Barker S.E., Newman Z.R., Norum A., Wheeler R.T. (2013) NADPH oxidase-driven phagocyte chemotaxis controls Candida albicans filamentous growth and prevents mortality. PLoS Pathog.
  • Gratacap R.L., Rawls J.F., Wheeler R.T. (2013) Mucosal candidiasis elicits NF-κB activation, proinflammatory gene expression and localized neutrophilia in zebrafish. Dis. Model. Mech. 6(5) 1260-1270.
  • Lionakis M.S., Swamydas M., Fischer B.G., Plantinga T.S., Johnson M.D., Jaeger M., Masedunskas A., Weigert R., Mikelis C., Wan W., Lee C-C.R., Lim J.K., Yang J.C., Laird G.M., Wheeler R.T., Alexander B.D., Perfect J.R., Gao J-L., Kullberg B-J., Netea M.G., and Murphy P.M. (2013) Chemokine Receptor CX3CR1 Promotes Early Fungal Clearance and Survival in Systemic Candidiasis by Inhibiting Apoptosis of Kidney Resident Macrophages J. Clin. Invest. 123(12):5035-51.
  • Tobin DM, May RC, Wheeler RT. (2012) Zebrafish: a see-through host and a fluorescent toolbox to probe host-pathogen interaction. PLoS Pathog. 2012 Jan;8(1):e1002349. Epub 2012 Jan 5. Read Abstract
  • Brothers K.M. and Wheeler R.T. (2012) Non-invasive imaging of zebrafish larvae as a model for disseminated candidiasis. J Vis Exp 30(65):pii 4051.
  • Brothers KM, Newman ZR, Wheeler RT (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. Read Abstract
  • 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 Pathogens (In Press)
  • 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.

Service

Section Editor: Translation Research, Current Fungal Infection Reports 2012-present

Review Editor: Frontiers in Immunotherapies and Vaccines, 2011-present

Peer Reviewer: PLoS Pathogens, Cell Host & Microbe, Nature Protocols, Molecular Microbiology, Eukaryotic Cell, Infection & Immunity, BMC Genomics, Archives of Medical Research, European Cytokine Network, Journal of Neuroscience Methods, Pathogens and Disease

Ad Hoc Grant Reviewer: (18 grants in previous 12 months) NIH Study Section AOIC (11/2012), NIH Study Section ZRG1/IDM-B (3/2013), NIH PTHE Study Section (6/2013), 5 other agencies.

Community Service

University Service

  • 2008 to 2016 — Small Animal Research Facility Oversight Committee
  • 2008 to 2016 — Graduate Program Admissions Committee
  • 2013 to 2016 — Advisor, Maine Society for Microbiology

Grants

  • 2008 to 2012 — $80,000.00 — “In vivo response to fungal infection.” from USDA
  • 2009 to 2014 — $450,000.00 — “Genomic interrogation and perturbation of natural fungal-host cell surface dynamics” from NIH/NCRR
  • 2010 to 2012 — $50,000.00 — “Characterization of radiation-induced inflammatory responses” from NASA/EPSCoR
  • 2012 to 2015 — $450,000.00 — “In vivo imaging of Candida-host interaction” from NIH/NIAID
  • 2012 to 2017 — $60,000.00 — “In vivo innate immune response to fungal infection” from USDA/Hatch
  • 2013 to 2014 — $25,000.00 — Characterization of radiation-induced inflammatory responses from NASA/EPSCoR
  • 2014 to 2019 — $500,000.00 — Investigators in the Pathogenesis of Infectious Disease from Burroughs Wellcome Fund
  • 2015 to 2016 — $10,000.00 — Research Scholar from Fulbright Commission