Coccidioides proteins as vaccine antigens and diagnostic biosignatures
John Galgiani, University of Arizona
Coccidioides spp. are fungal pathogens that normally cause a pneumonia associated with considerable morbidity and attendant economic or medical care costs. Some infections produce respiratory failure, soft tissue abscesses, osteomyelitis or meningitis. Even in otherwise healthy persons, inhalation of a single spore is sufficient to result in death from one or more of these complications, and this degree of infectivity was responsible, in part, for past development programs by the U.S. and the Soviet Union to use Coccidioides spp. as biological weapons. Coccidioides spp., recently classified as Category C select agents, are also considered emerging public health pathogens. Because coccidioidal infection so often produces life-long protection against re-infection, it is likely that a preventative vaccine could be effective. A screening program of approximately two dozen coccidioidal proteins identified a recombinant vaccine that was recommended for clinical trials. However, manufacturing difficulties related to the antigen's specific sequence has impeded its further development. In this project, we will use in vitro protein expression to permit antigen screening on a larger scale as a means of identifying equally protective antigens that are more amenable to formulation. Our goal is to identify a second-generation recombinant vaccine candidate that could be developed for clinical testing. We will also develop antigen-detecting assays as a more sensitive diagnostic tool for early Valley Fever.
Using comparative genomics to identify Coccidioides virulence factors
Anita Sil, UC San Francisco/John Taylor, UC Berkeley
The environmental fungal pathogens Coccidioides and Histoplasma have been proposed as agents of warfare because of their easy availability, stability of spores, and infection by aerosolization. Therefore, more knowledge about the pathogenesis of these closely related organisms is critical to biodefense. Each of these organisms converts to a parasitic form in mammalian hosts after inhalation of infectious spores from the soil. We aim to understand their pathogenesis by identifying fungal genes that promote disease and manipulate the host. Use of a comparative genomics approach to analyze Coccidioides and Histoplasma is likely to be fruitful because of their close evolutionary relationship and the similarities of their lifestyles in the soil and the host. We will take advantage of information inherent in the genomes of these pathogens and related fungi to generate a set of genes most likely to influence disease. This comparative approach will reveal genes that have undergone strong positive selection in these fungal pathogens. Additionally, we will identify conserved genes in Coccidioides and Histoplasma that are implicated in the conversion to the parasitic form of each organism by virtue of their role in Histoplasma. These studies will allow us to prioritize a testable number of candidate virulence genes that will be assessed for their role in pathogenicity in the mouse models of Coccidioides and Histoplasma infections.