ABOUT THE RESEARCHER

OVERVIEW

The Koehler laboratory investigates how the fungus Candida albicans, which lives harmlessly on mucous membranes of healthy humans but causes deadly invasive infections in immunocompromised patients, uses different cell types to grow and spread. This opportunist, the most common cause of invasive fungal infections, switches frequently between growth as round or oval budding yeast, and growth as long, spear-shaped hyphal or pseudohyphal filaments. Hyphal cells can penetrate through host tissues like drills, and yeast can float easily through the bloodstream to initiate new areas of infection.

The many different environmental conditions encountered by C. albicans during its growth on various mucous membranes including of the mouth, throat, gastrointestinal tract and vagina, and during invasion of the blood stream and of deep organs, require rapid and highly flexible responses from the fungus if it is to survive and to multiply. Switching between cell types is part of these responses. In addition, during lack of nutrients and attack by immune cells the fungus must target its energy resources to survival programs, while it must take advantage of favorable conditions by turning on growth and proliferation programs.

The laboratory began a systematic investigation of how C. albicans switches between cell types, with a transposon mutant collection, generated with a novel mariner transposon and screened for mutants which fail to normally produce lateral yeast from hyphae. Mutants in several genes involved in DNA replication were found, among them a homolog of pescadillo. It was shown that this gene, essential in all eukaryotes, is essential in C. albicans yeast but that hyphae tolerate its depletion. Pescadillo was found to be an effector of Target of Rapamycin (TOR) signaling.

TOR signaling coordinates responses of eukaryotic cells to extracellular conditions, favorable or stressful. As TOR is predicted to be critical for an opportunistic pathogen which must multiply when nutrients are ample, yet survive intense immune system and starvation stress, the laboratory is also analyzing novel components of TOR signaling identified in a screen with the same mutant collection. In addition we are using reverse genetics to study TOR signaling and its interactions with other pathways important for coordinating cellular responses to nutritional and stress conditions.

BACKGROUND

Dr. Koehler obtained her M.D. from Heidelberg University in Germany. She trained in pediatrics at the Heidelberg Children’s Hospital and at Boston Children’s Hospital. She then joined the Boston Children’s Hospital Infectious Disease Division as a trainee and subsequently as staff. She received postdoctoral research training in the laboratory of Dr. Gerald Fink at the Whitehead Institute. Her clinical areas of particular interest are fungal infections, and immigrant health.

Selected Publications

  1. Shen J., Guo W., Köhler J.RCaNAT1, a heterologous dominant selectable marker for transformation of C. albicans and pathogenic non-albicans Candida species, Infect. Immun. 2005, 73 (2): 1239-1242
  2. Shen J., Cowen L.E., Griffin A.M., Chan L., Köhler J.R. The Candida albicans pescadillo homolog is required for normal hypha-to-yeast morphogenesis and yeast proliferation. Proc. Natl. Acad. Sci. USA. 2008.105(52):20918-23.
  3. Uppuluri, P., Ashok K. Chaturvedi, A.K., Srinivasan, A., Banerjee, M., Ramasubramaniam, A., Köhler, J.R., Kadosh, D., Lopez Ribot, J. Dispersion as an Important Step in the Candida albicans Biofilm Developmental Cycle, PloS Pathogens, 2010, 6(3): e1000828
  4. Uppuluri, P., Ashok K. Chaturvedi, A.K., Jani, N., Pukkila-Worley, R., Monteagudo, C., Mylonakis, E., Köhler, J.R., Lopez Ribot, J. Physiologic Expression of the Candida albicans Pescadillo Homolog Is Required for Virulence in a Murine Model of Hematogenously Disseminated Candidiasis. Eukaryotic Cell. December 2012 11:12 1552-1556
  5. Köhler JR, Sola-Visner M. The silent crisis: children hurt by current immigration enforcement policies. JAMA Pediatr. 2014 Feb 1;168(2):103-

PUBLICATIONS

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  1. Phosphate in Virulence of Candida albicans and Candida glabrata. J Fungi (Basel). 2020 Mar 26; 6(2). View abstract
  2. Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for Candida albicans Cell Wall Maintenance. mBio. 2020 03 17; 11(2). View abstract
  3. Medical Deferred Action - Living on Borrowed Time. N Engl J Med. 2019 Oct 24; 381(17):1601-1603. View abstract
  4. Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation. mSphere. 2019 09 11; 4(5). View abstract
  5. Candida albicans Dispersed Cells Are Developmentally Distinct from Biofilm and Planktonic Cells. mBio. 2018 08 21; 9(4). View abstract
  6. Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog. 2018 07; 14(7):e1007076. View abstract
  7. The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway. mSphere. 2017 Nov-Dec; 2(6). View abstract
  8. The Candida albicans TOR-Activating GTPases Gtr1 and Rhb1 Coregulate Starvation Responses and Biofilm Formation. mSphere. 2017 Nov-Dec; 2(6). View abstract
  9. Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems. Sci Immunol. 2017 Sep 22; 2(15). View abstract
  10. Fungi that Infect Humans. Microbiol Spectr. 2017 06; 5(3). View abstract
  11. Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. Proc Natl Acad Sci U S A. 2017 06 13; 114(24):6346-6351. View abstract
  12. Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, Blocks Candida albicans Morphogenesis, and Is Effluxed via Yor1 and Circuitry Controlled by Zcf29. Antimicrob Agents Chemother. 2016 12; 60(12):7468-7480. View abstract
  13. Antagonism of Fluconazole and a Proton Pump Inhibitor against Candida albicans. Antimicrob Agents Chemother. 2016 Feb; 60(2):1145-7. View abstract
  14. Ribosomal protein S6 phosphorylation is controlled by TOR and modulated by PKA in Candida albicans. Mol Microbiol. 2015 Oct; 98(2):384-402. View abstract
  15. The silent crisis: children hurt by current immigration enforcement policies. JAMA Pediatr. 2014 Feb; 168(2):103-4. View abstract
  16. Physiologic expression of the Candida albicans pescadillo homolog is required for virulence in a murine model of hematogenously disseminated candidiasis. Eukaryot Cell. 2012 Dec; 11(12):1552-6. View abstract
  17. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2818-23. View abstract
  18. The Candida albicans pescadillo homolog is required for normal hypha-to-yeast morphogenesis and yeast proliferation. Proc Natl Acad Sci U S A. 2008 Dec 30; 105(52):20918-23. View abstract
  19. Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog. 2008 Feb 08; 4(2):e35. View abstract
  20. CaNAT1, a heterologous dominant selectable marker for transformation of Candida albicans and other pathogenic Candida species. Infect Immun. 2005 Feb; 73(2):1239-42. View abstract
  21. Mos10 (Vps60) is required for normal filament maturation in Saccharomyces cerevisiae. Mol Microbiol. 2003 Sep; 49(5):1267-85. View abstract
  22. Nonfilamentous C. albicans mutants are avirulent. Cell. 1997 Sep 05; 90(5):939-49. View abstract
  23. Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc Natl Acad Sci U S A. 1996 Nov 12; 93(23):13223-8. View abstract