Alternative Carbon Utilization as a Virulence Determinant for Candida albicans
Robert Bryan Williams, BS (Advisor: Michael C. Lorenz, PhD)
Candida albicans is a polymorphic unicellular fungus that has evolved to proficiently colonize and infect mammals. A common constituent of the microbiome in the GI tract, mouth, vagina, and skin, C. albicans is also an opportunistic pathogen capable of causing a variety of mucosal infections and the life-threatening disseminated candidiasis. Systemic C. albicans infections are a serious and growing issue; the fungus is the fourth most common cause of nosocomial bloodstream infections which has a mortality rate reaching 50%. As antifungal resistance continues to rise, it is critical that we understand the molecular basis of disseminated fungal infections.
The phagocytes of the immune system are especially important for preventing disseminated infection. Macrophages are employed to clear pathogens in the harsh environment of a phagosome, but C. albicans, as an adaptable opportunist, is capable of surviving macrophage attack to continue dissemination. The Lorenz Lab and other leading labs in the field have identified that C. albicans rapidly adapts to the macrophage phagosome by upregulating alternative carbon utilization processes. Three alternative carbon utilization pathways particularly contribute to C. albicans pathogenesis: carboxylic acids, amino acids, and N-acetylglucosamine. Studied individually, each pathway appears to equally contribute to pathogenesis, although mutants defective in any one carbon pathway display only modest attenuation.
The strategy for my thesis research was to take a holistic approach to understand the implications of alternative carbon utilization for both macrophage interactions and disseminated candidiasis. Recent advancements in genetic manipulation technologies allowed for the rapid generation of mutants with several deletions, permitting for the study of multiple alternative carbon pathways simultaneously. Indeed, each alternative carbon pathway is both genetically and physiologically distinct; mutants defective in multiple alternative carbon pathways are significantly attenuated compared to the single pathway mutants, suggesting that each carbon pathway individually contributes to pathogenesis. Moreover, these carbon sources are more than energy sources for the pathogen, serving as signals to its microenvironments and benefiting C. albicans in distinct manners by promoting resistance to host-relevant stressors and cell wall rearrangements that allow the fungus to evade immune cells. Here, I argue that alternative carbon utilization is an essential virulence regulator for C. albicans, required for the activation of several virulence determinants that contribute to disseminated candidiasis.
- Michael C. Lorenz, PhD, Chair
- Shane R. Cunha, PhD
- Nicholas R. De Lay, PhD
- Anne-Marie Krachler, PhD
- Ambro van Hoof, PhD