The fungus Candida albicans has a unique relationship with human beings
Among ~100,000 known species of fungi, C. albicans is the only one that is both a major human pathogen and a normal commensal.  This observation alone suggests that this organism has evolved unique properties to adapt to the human niche.  We seek to understand these properties as a way of uncovering mechanisms of fungal pathogenesis as well as novel aspects of mammalian biology.

Most human beings are harmlessly colonized with C. albicans in childhood.  C. albicans normally resides in the gastrointestinal tract, in the genitourinary tract, and on the skin of humans and other warm-blooded animals.  Patients who are susceptible to invasive and disseminated C. albicans infections include those who have been treated with immunosuppressive drugs (that diminish immune barriers to infection), intravenous catheters (that damage physical barriers to infection), and/or long courses of antibiotics (that kill bacterial competitors).  In such hosts, C. albicans can proliferate in the bloodstream and virtually any other tissue, including the brain.

Genetic resources
We have taken a genetic approach to understanding C. albicans, which was non-trivial because of its obligate diploid genome.  Nonetheless, using high-throughput knockout methods, we generated a large library of C. albicans targeted null mutants affecting ~700 hand-selected genes.  These were systematically screened for three properties: a) competitive fitness in the host; b) the yeast-to-hyphal morphological transition; and c) rate of proliferation in vitro.  137 mutants exhibited consistent defects in infection, and 63 among these had no corresponding defects in the in vitro assays.  This subset of infectivity-specific mutants is likely to affect specific effectors of virulence.

Studying interactions of a C. albicans glycolipid virulence effector with the mammalian immune system
We have already identified one such effector molecule. Using a combination of genetics, biochemical purification, and mass spectrometry, we have found that four of the infectivity-specific mutants affect a pathway for biosynthesis of a fungal-specific sphingolipid molecule that is also required for virulence.  In close collaboration with the immunology group at UCSF, we are currently testing the hypothesis that this sphingolipid modulates the host innate immune system in a manner that is advantageous to the pathogen.  Specifically, we seek to identify the host cell type and receptor(s) targeted by this lipid and to understand how its recognition modifies host immune responses to the pathogen’s advantage. 

Future directions
We are pursuing a number of additional mutants identified in our large-scale screens including factors involved in iron acquisition and proteins displayed on the cell surface that are poised to interact directly with the host.  We also seek to test the roles of these factors in the commensal lifestyle to determine whether it represents a distinct mode of interaction with the host.

The Noble lab
The laboratory is located on the 4th floor of HSE, and is adjacent to a number of other laboratories studying aspects of microbial pathogenesis and host responses.  E-mail Suzanne.Noble[at]ucsf.edu for rotation inquiries.