Washington University, St. Louis, MO

The fungal cell wall is an essential organelle which is composed of various carbohydrates and proteins, and is vital for maintaining cell integrity against various chemical, physical and biological stressors. Host defense systems are often directed against cell wall components, and because the components of the fungal wall are not found in the mammalian host, the wall has been recognized as an ideal antifungal target. The cell wall of the fungal pathogen Cryptococcus neoformans is considerably more complex than other fungal systems, and the Lodge lab is using genetics, biochemistry and genomics to understand the function of the fungal cell wall, including biosynthesis, localization and linkage of carbohydrate and protein components, regulation of signal transduction pathways, and interactions with the host.

Dr. Lodge and her laboratory have demonstrated that chitosan is an abundant component of Cryptococcus cell walls, both during vegetative growth and during infection of mouse lungs. She has explored genes that contribute to chitosan production, and shown that only one of eight chitin synthases, and one of three putative chitin synthase regulators substantially impact chitosan levels. In addition, she has shown that three of four potential polysaccharide deacetylases produce chitosan, and are currently investigating the mechanism of chitin deacetylation. These deacetylases are cell wall GPI-anchored mannoproteins, but in contrast to GPI-mannoproteins in S. cerevisiae, they are not linked to the wall through a GPI anchor but are non-covalently attached. Dr. Lodge has developed multiple independent strains of Cryptococcus that lack chitosan and shown that chitosan is required for persistence and virulence. She is currently exploring the role of chitosan during infection.

Multiple signal transduction pathways detect the environment and are used by fungi to respond to stresses. Dr. Lodge has shown that the PKC1 pathway (aka the cell integrity pathway) has a role in response to antimicrobial defenses that are found in the human host, including oxidative and nitrosative stresses, and chitinases. She and her lab are exploring the regulators of the PKC1 pathway and the kinases within the pathway that are necessary for responses to different signals.