Metabolic regulation and spatio-temporal aspects of fungal virulence in situ

Humans are host to a wide spectrum of commensal microorganisms collectively known as the human microflora.

The microflora is largely composed of prokaryotic bacteria, however, eukaryotic fungi are also major components, with Candida spp. dominating.

Many species of Candida are opportunistic pathogens that can cause life threating infections in immune compromised individuals.

As the incidence of candidiasis is quite low in healthy populations, environmental factors, such as interactions with the primary immune cells play critical roles.

The Ljungdahl laboratory has recently identified mitochondrial proline catabolism as critical for inducing and energizing filamentous growth, a virulence feature that underlies evasion from macrophages and the ability to invade across endo- and epithelial barriers.

Building on this knowledge, we define three aims: 1) Fully characterize the metabolic control of proline-dependent fungal virulence, specifically the role of mitochondrial-localized processes that are critical to fungal cell survival in hosts; 2) Visualize the spatio-temporal aspects of C. albicans infections in the kidney of a living mammalian host and define host-pathogen interactions using advanced intravital and STED microscopy and spatio-transcriptomic analysis; and 3) Define the virulence properties of multidrug resistant Candida auris.

The anticipated results are critical for novel therapeutic strategies in the expanding population of immune compromised individuals.