Fungal Virulence: Identifying the factors that control virulence and the growth in parasitic form of Coccidioides

Abstract
This Project will focus on the pathogen by undertaking transcriptomic, proteomic and genome-scale studies of
Coccidioides species. Coccidioides species, C. immitis and C. posadasii, grow as a mycelium in the soil and
differentiate into a unique round structure called a spherule in the mammalian host – a hallmark of their
pathogenicity. Spherules enlarge and divide internally to form endospores which are released after about 4 days
in the mammalian host. The mechanisms of differentiation into spherules and virulence factors of Coccidioides
remain largely unknown. We are intrigued by the hypothesis that spherule-enriched genes and spherule surface-
attached proteins are major players of the immune evasion strategies adopted by the pathogen. Therefore, in
this Project, our overall goal is to identify genes/proteins that may play a role in (1) controlling transition from
environmental-to-parasitic growth or (2) directly interacting with the host to subvert immune responses. We will
take functional genomics and proteomic approaches to identify factors (i.e. transcriptional regulators) that are
required for the expression of spherule-specific genes and endospore-specific genes and characterize them for
their importance in spherule growth and spherule-specific gene expression profiles. In addition, we will identify
fungal genes that are important for response to susceptible and resistant murine hosts, identify the secreted,
surface-attached and/or GPI-anchored proteins from Coccidioides spherules, and generate knockout mutants of
the candidate genes, which will be selected based on these transcriptomic and proteomics studies and our
preliminary data. Mutants that show significant difference in eliciting cytokine response in cell culture will be
prioritized to be tested for virulence phenotypes in mouse model of coccidioidomycosis under the activities
planned in the Model Organism Core. Results of these experiments will reveal genes/proteins that are involved
in regulating the parasitic growth of Coccidioides and shed light onto the molecular details of interactions between
host and the pathogen.

Grant Number: 5U19AI166059-05
NIH Institute/Center: NIH
Principal Investigator: Sinem Beyhan