Jennifer Lodge
Associate Professor of Biochemistry and Molecular Biology
Associate Dean for Research

EDUCATION:
Ph.D., 1988, Washington University

MEMBERSHIPS:
American Society for Microbiology
American Society for Biochemistry and Molecular Biology

HONORS:
Burroughs Wellcome New Investigator Award in Molecular Pathogenic Mycology

RESEARCH SUMMARY:

AIDS has contributed to a significant increase in the population of immunocompromised patients who are exquisitely vulnerable to fungal infections. In particular, Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis and is a leading cause of death in immunocompromised patients. Our laboratory is interested in understanding fungal pathogenesis and identifying novel virulence genes in C. neoformans. The genome of C. neoformans has been sequenced, and we are using post-genomic approaches to understanding the molecular basis for pathogenesis and for discovery of new antifungal targets.

We are using proteomics to identify proteins that are regulated during pathogenesis with an emphasis on oxidative and nitrosative stresses. Proteins that are upregulated during pathogenesis are selected for gene-specific knockouts. Using this approach, we have shown that thiol-peroxidases have increased expression at 37°C vs. 25°C and on exposure to peroxidases. Gene deletion of one of the C. neoformans thiol peroxidase causes a peroxide-sensitive, NO-sensitive, temperature-sensitive and avirulent phenotype. We are currently other proteins from the thioredoxin and glutathione pathways for their contribution to protection from oxidative and nitrosative stresses and virulence.

In addition, our laboratory has initiated a systematic gene deletion project for C. neoformans. We have begun deleting genes involved in cell wall structure or biosynthesis and have developed in vitro screens for cell wall integrity. Each gene deletion is “tagged” with a unique DNA sequence that allows us to follow the abundance of the mutant in a pool of mutants. Using these tags we can test 48 mutants in a single mouse for their ability to proliferate. We have identified several genes that are clearly important for cell wall integrity and virulence.

 
Two-dimensional gel analysis of C. neoformans grown at either 25°C or 37°C.
Spot 1 (Tsa1) and Spot 2 (Tsa3) proteins which are differentially expressed at 37°C, are indicated with arrows. The pH gradient (4-7) that was used for the first dimension is shown along the bottom, and the size markers for the second dimension are shown along the right side in kD.