Candida albicans is a commensal species that occupies diverse niches of the human body. It is
also a prevalent opportunistic pathogen, being a frequent cause of debilitating mucosal infections and
life-threatening systemic infections. In many cases, the commensal form is responsible for seeding
systemic disease, which is often precipitated by a breakdown in host immunity. Despite its clinical
importance, there remains limited understanding of commensal interactions between C. albicans and the
host, or the fungal traits that influence invasion and disease during a disseminated infection.
One of the most notable attributes of C. albicans is its ability to grow in different heritable states
and morphological forms. The ability to transition between different phenotypic states can enable
adaptation to host niches and modulate interactions with the immune system. Epigenetic mechanisms
have been shown to regulate heritable switching between cell states, yet it is not known why only some
clinical isolates undergo certain phenotypic switches, or how transitions between cell states determines
outcomes in interactions with the host.
We now propose a genetic mechanism underlies an important cell state transition in C. albicans
that impacts both commensal and pathogenic behavior. C. albicans is a heterozygous diploid species
and we made the unexpected observation that many clinical isolates are poised to undergo
differentiation due to being functionally heterozygous for a key transcription factor. Furthermore, such
heterozygous strains frequently lose the functional copy of the transcription factor gene both during
laboratory culture and during infection of the host. The direct consequence of this transformative event is
generation of a cell state that is hypercompetitive both in commensal and disseminated infection models.
The goals of the current project are (1) to establish that changes in a master transcription factor
gene direct a clinically relevant phenotypic switch, (2) to define whether the transcription factor gene
represents a genomic hotspot for mutagenesis and/or recombination events, and (3) to examine cell
state transition events during infection of the mammalian host, as well as the properties of different cell
states that define fungal behavior in commensal and pathogenic models of infection.
The proposed studies will provide new insights into how C. albicans adapts to different niches in
the host, including an unexpected mechanism by which genetic polymorphisms and genomic plasticity
combine to drive cell differentiation. These experiments will establish an important paradigm for C.
albicans biology, as it is likely that other heterozygous loci are similarly primed for genetic events that
drive adaptation in the host.