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 b-glucan is present throughout the cell wall of Candida, but as we discovered, the pathogen masks b-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 b-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

The innate arm of the immune system (macrophages, dendritic cells, and neutrophils) is responsible for clearing Candida from the body, and in addition signals to the adaptive immune system (T-cells and B-cells) to initiate long-lived immunity. We have recently used a high throughput genomics approach to identify cellular components of dendritic cells that recognize and respond to Candida. This approach is based on hijacking pre-existing cellular machinery to target elimination of specific gene products through RNA interference (RNAi). We screened a targeted set of genes and identified new candidate regulators of response to fungi. We are now validating these candidates and exploring how they affect both recognition and subsequent responses to fungi.

Publications

• 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.

Community/University Service

• to — Community Service —
• to — Community Service —
• 2008 to — University Service — Small Animal Research Facility Oversight Committee
• 2008 to — University Service — Graduate Program Admissions Committee

Grants

• 2008 to 2012 — — In vivo immune response to fungal infection from USDA/MAFES
• 2009 to 2014 — 680000.00 — Genomic interrogation and perturbation of natural fungal-host cell surface dynamics from Maine IDeA Network-NIH/NCRR
• 2009 to 2010 — 45000.00 — Effect of Caspofungin-mediated beta-glucan exposure on fungal clearance from Merck & Co., Inc.
• 2009 to 2014 — 290000.00 — Maine Regional Flow Cytometry Collaborative from Maine Technology Institute