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.
About Julia Koehler
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.
Shen J., Guo W., Köhler J.R. CaNAT1, a heterologous dominant selectable marker for transformation of C. albicans and pathogenic non-albicans Candida species, Infect. Immun. 2005, 73 (2): 1239-1242
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.
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
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
Köhler JR, Sola-Visner M. The silent crisis: children hurt by current immigration enforcement policies. JAMA Pediatr. 2014 Feb 1;168(2):103-