C. albicans is the most common human fungal pathogen yet its virulence mechanisms are not fully understood. Here, I submit a revised application for a K08 award that presents a novel approach for the study of C. albicans pathogenesis. Since my original submission, I have conducted full-time research for 15 months in the laboratories of Dr. Eleftherios Mylonakis and Dr. Frederick Ausubel at Massachusetts General Hospital (MGH). During this time, I have published a first-author original research paper (Eukaryotic Cell, cover), contributed to another study (Journal of Experimental Medicine) and was first-author on a review article. Additionally, I have obtained grant support from the Irvington Institute Fellowship Program of the Cancer Research Institute, the MGH Executive Committee on Research Fund for Medical Discovery, the NIH Loan Repayment Program and a NIH T32 grant. These experiences and successes demonstrate my desire to have a career in academic medicine and indicate that I have the potential to develop into an independent scientist. The faculty who support this application are among the most recognized mentors in academia, each with an impressive record of fostering the development of independent investigators. My co-mentors, Dr. Mylonakis (Assistant Professor of Medicine) and Dr. Ausubel (Professor of Genetics), each bring complementary areas of expertise to this project. I have also formed a Scientific Advisory Panel composed of my co-mentors, Dr. Stephen B. Calderwood (Morton N. Swartz Professor and Division Chief) and Dr. Joseph Heitman (James B. Duke Professor and Department Chair) to monitor my progress. The research environment is therefore uniquely suited to facilitate the completion of the proposed career development plan. For these studies, I will use the model host Caenorhabditis elegans to determine the mechanisms by which C. albicans activates epithelial immunity. In nature, nematodes encounter numerous threats from ingested pathogens, which have provided a strong selection pressure to maintain a coordinated defense response. I was the first to show that C. elegans can be used to accurately model key aspects of human candidiasis. I also found that the nematode mounts a targeted antifungal response in a genome-wide transcription profiling analysis. Here, I use these data to characterize the signaling mechanisms of two virulence pathways of central importance to nematode immunity (Aim 1). I also outline an in-depth characterization of a gene I identified in a screen for novel innate immune receptors (Aim 2). Lastly, I propose a unique screen for novel immune response genes using a tool that will maximize the yield for uncharacterized innate immune response elements (Aim 3). These experiments offer the first assessment of the C. elegans innate immune response to an intestinal fungal pathogen and address questions of fundamental importance to host-pathogen interactions. Candida albicans is found in the intestine of virtually all healthy humans. However, this fungus can cause life- threatening infections, particularly in critically ill patients or in individuals with compromised immune systems. The proposed studies use the model host Caenorhabditis elegans to examine the mechanisms employed by the innate immune system to defend against C. albicans infection.

Public Health Relevance

Candida albicans is found in the intestine of virtually all healthy humans. However, this fungus can cause life- threatening infections, particularly in critically ill patients or in individuals with compromised immune systems. The proposed studies use the model host Caenorhabditis elegans to examine the mechanisms employed by the innate immune system to defend against C. albicans infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI081747-04
Application #
8465793
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Duncan, Rory A
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$137,025
Indirect Cost
$10,150
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Pukkila-Worley, Read; Feinbaum, Rhonda L; McEwan, Deborah L et al. (2014) The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification. PLoS Pathog 10:e1004143
Chan, Brian T; Hohmann, Elizabeth; Barshak, Miriam Baron et al. (2013) Treatment of listeriosis in first trimester of pregnancy. Emerg Infect Dis 19:839-41
Pukkila-Worley, Read; Ausubel, Frederick M (2012) Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24:3-9
Pukkila-Worley, Read; Ausubel, Frederick M; Mylonakis, Eleftherios (2011) Candida albicans infection of Caenorhabditis elegans induces antifungal immune defenses. PLoS Pathog 7:e1002074