Figure 1. The yeast C. albicans can proliferate in multiple sites of the human body. (A) morphology of C. albicans cells observed under the microscope. (B) Morphology of a C. albicans colony grown on standard agar plates. (C) Cartoon illustrating the different sites of the human body where C. albicans typically proliferates as a commensal organism. The same yeast can also behave as an aggressive pathogen, colonizing virtually every internal organ and leading to death in as many as 50% of bloodstream infections.
Figure 2. Core transcriptional circuit governing the ability of C. albicans to proliferate in mammalian hosts. Orange circles are transcription regulators; arrows depict protein-DNA interactions as mapped by ChIP. The phenotypes ascribed to each regulator are indicated in green/red. The highly interwoven topology of the circuit suggests that commensalism and pathogenicity are intertwined traits. Modified from Pérez et al., 2013.

Our group is interested in understanding gene regulatory circuits: their logic and underlying structure, how they control specific traits, and how they change over evolutionary timescales. We focus our research on Candida albicans, the most prominent fungal species residing in healthy humans and also the major cause of serious fungal infections. Dissecting the regulatory circuitry that allows the yeast C. albicans to colonize different sites of the human body serves as a model to gain insights into (1) the tactics employed by members of our microbiota to proliferate as harmless commensals and (2) what goes awry when some of these microbes become life-threatening pathogens.

Regulatory circuits underlying C. albicans proliferation in disparate host niche

C. albicans has the ability to proliferate in multiple locales of the human body: skin, mouth, gastrointestinal (GI) and genitourinary tracts. This diversity of sites raises the question of whether C. albicans uses overlapping or largely independent genetic programs to colonize each niche. We have explored the gene repertoire involved in GI tract colonization and bloodstream infection and plan to incorporate additional mouse models to capture the breadth of niches where this organism proliferates. Combining genetic screens in these animal models with genome-wide molecular biology approaches (RNA-seq, ChIP-seq) will reveal not only genes and cellular functions, but also the strategies that the fungus uses to grow and cause disease in each locale.

Role of the host microbiota in C. albicans gut colonization

The microorganisms that live in our GI tract interact not only with the human host but also with thousands of other microbial species. Global studies of the composition and dynamics of our microbiota indicate that there are strong interdependencies among specific groups of microbes; therefore, it is likely that, just as the status of the immune system of the host influences the severity of Candida infections, the composition of the microbiota also plays a role in C. albicans’ acting as pathogen. We plan to use germ-free mice to explore this hypothesis and learn to what extent the regulatory circuitry that C. albicans employs to colonize the GI tract is designed to cope with, or to rely on, other members of the microbiota.

Signals sensed by microbes in the host

C. albicans as well as other microbes residing in the human host must be able to continuously gauge their surroundings and adjust their behavior accordingly to prosper. We are interested in learning what signals, either chemical or physical, denote given environments in the host and, thus, are sensed by the fungus. A first step in this direction is to experimentally determine what sensors and signal transduction pathways feed into C. albicans “pathogenesis” genes through the use of reporter genes. The extensive body of knowledge on the signal transduction pathways operating in the model yeasts S. cerevisiae and S. pombe guides this effort.