We seek to understand the molecular mechanisms of commensalism in Candida albicans, a normal component of the human microbiome as well as the most common cause of devastating fungal infections. Studies of C. albicans strains recovered from patients with Candida disease syndromes have demonstrated that the vast majority of disseminated infections arise from patients'own commensals (Odds et al., 2006). However, we have scant understanding of the molecular basis of commensalism or the commensal-to-pathogen transition. We recently generated two large collections of more than 750 homozygous gene deletion mutants of this obligate diploid organism (Homann et al., 2009) (Noble et al., 2010). By means of a genetic screen of the mutants in a mouse model of bloodstream infection, we identified multiple novel virulence factors including a fungal-specific sphingolipid (Noble et al., 2010) and a novel transcriptional activator of iron uptake genes (Chen, Pande et al., submitted). We now propose to use the same genetic resource to screen for commensalism factors in a mouse model of gastrointestinal commensalism. To this end, our pilot studies have already revealed a novel opaque- independent role for master regulator of the white-to-opaque phenotypic transition, Wor1, in promoting commensal infections of the gut. We hypothesize that C. albicans possesses distinct genetic programs for commensalism and virulence, and comparison of the results from the commensalism and virulence screens will directly test this hypothesis. The results will significantly enhance an understudied area research and promise to reveal opportunities for prevention and treatment of highly morbid of C. albicans infections.

Public Health Relevance

This project seeks to understand how Candida albicans persists as a commensal organism in the mammalian gastrointestinal tract. This is relevant to public health because the commensal reservoir of this ubiquitous human fungus is the source of disseminated candidiasis, a common and highly morbid infection among hospitalized patients. An improved understanding of the commensal lifestyle and the mechanisms underlying the commensal-to-pathogen switch could lead to novel therapies for prevention as well as treatment of these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI099659-01
Application #
8282366
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2012-02-15
Project End
2014-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$193,125
Indirect Cost
$68,125
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pande, Kalyan; Chen, Changbin; Noble, Suzanne M (2013) Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism. Nat Genet 45:1088-91