Our long-term objective is to develop methods to prevent and treat coccidioidomycosis, a systemic fungal disease of otherwise healthy humans caused by the fungi Coccidioides immitis and Coccidioides posadasii. The collaborating investigators are John Taylor and Garry Cole, directors of laboratories that study Coccidioides molecular developmental and evolutionary biology, respectively. Our goal in this proposal is to focus the tools of comparative genomics and gene expression on Coccidioides to identify genes important to pathogenicity and virulence. Two of our findings underlie our proposal: 1) disruption of genes known to be important to the pathogenicity of Coccidioides reduces its virulence in mammals, and 2) Coccidioides shows genetic variation among five geographic populations. The availability of complete, annotated genomes of each /coccidioides species and the genome of their non-pathogenic relative, Uncinocarpus reesii, is a major pillar of support for our project. We can greatly increase the number of targets for therapy or prevention by searching the genome for pathogenicity genes, while accounting for natural variation. We will evaluate our hypotheses about these genes by virulence tests in mice.
Our specific aims are to: identify genes unique to Coccidioides as compared to Uncinocarpus, identify genes that show positive selection between Coccidioides species and compared to Uncinocarpus, and identify genes in Coccidioides with significant transcription differences between the saprobic and parasitic phases, both in vitro and in vivo. From this cadre of unique genes which are under positive selection and upregulated during the parasitic phase, we will identify a pool of putative pathogenicity genes that can we will test by assessing virulence in mice of the wild-type strain, the WT strain in which the gene of interest has been knocked out, and the KO strain with the gene of interest replaced. Via existing collaboration, our laboratories have studied and published on natural selection of Coccidioides pathogenicity genes and assessed transcription in the saprobic and parasitic phases. Relevance to public health: Nearly 10% of Americans live in areas endemic to coccidioidomycosis, and approximately 5% of those infected develop life-threatening disease. Symptomatic infections confer long term immunity, so vaccination is possible. Likewise, virulence is reduced when pathogenicity genes are disabled, which indicates that pharmaceutical targeting of these gene products should be efficacious.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070891-04
Application #
7800260
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$406,524
Indirect Cost
Name
University of California Berkeley
Department
Other Basic Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Wise, Hua Zhang; Hung, Chiung-Yu; Whiston, Emily et al. (2013) Extracellular ammonia at sites of pulmonary infection with Coccidioides posadasii contributes to severity of the respiratory disease. Microb Pathog 59-60:19-28
Whiston, Emily; Zhang Wise, Hua; Sharpton, Thomas J et al. (2012) Comparative transcriptomics of the saprobic and parasitic growth phases in Coccidioides spp. PLoS One 7:e41034
Hung, Chiung-Yu; Wise, Hua Zhang; Cole, Garry T (2012) Gene disruption in Coccidioides using hygromycin or phleomycin resistance markers. Methods Mol Biol 845:131-47
Hung, Chiung-Yu; Hurtgen, Brady J; Bellecourt, Michael et al. (2012) An agonist of human complement fragment C5a enhances vaccine immunity against Coccidioides infection. Vaccine 30:4681-90
Sanchez, Carlos J; Hurtgen, Brady J; Lizcano, Anel et al. (2011) Biofilm and planktonic pneumococci demonstrate disparate immunoreactivity to human convalescent sera. BMC Microbiol 11:245
Gilbert, Luz B; Kasuga, Takao; Glass, N Louise et al. (2011) Array CGH phylogeny: how accurate are comparative genomic hybridization-based trees? BMC Genomics 12:487
Gonzalez, Angel; Hung, Chiung-Yu; Cole, Garry T (2011) Absence of phagocyte NADPH oxidase 2 leads to severe inflammatory response in lungs of mice infected with Coccidioides. Microb Pathog 51:432-41
Gonzalez, Angel; Hung, Chiung-Yu; Cole, Garry T (2011) Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages. Microb Pathog 50:100-8
Gonzalez, Angel; Hung, Chiung-Yu; Cole, Garry T (2011) Nitric oxide synthase activity has limited influence on the control of Coccidioides infection in mice. Microb Pathog 51:161-8
Hung, Chiung-Yu; Gonzalez, Angel; Wuthrich, Marcel et al. (2011) Vaccine immunity to coccidioidomycosis occurs by early activation of three signal pathways of T helper cell response (Th1, Th2, and Th17). Infect Immun 79:4511-22

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