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Joan McEwen Associate Professor, Department of Geriatrics and Department of Microbiology & Immunology Mycology Research Interest: Virulence mechanisms of Histoplasma capsulatum Ph.D ., Albert Einstein College of Medicine Postdoctoral , University of Colorado Phone: (501) 257-5559 Research Description Virulence mechanisms of Histoplasma capsulatum - Histoplasma capsulatum is a dimorphic fungal pathogen of humans. The mycelial form of the fungus is found worldwide in soil. When inhaled into the lungs of animal hosts, the mycelial forms convert to budding yeast cells, which exist in a host mainly as an intracellular parasite of macrophages. The organisms are exposed to mammalian host microbicidal mechanisms that include production of reactive oxygen species by neutrophils and macrophages, yet they are relatively unaffected by these host efforts. We hypothesize that existence of robust anti-oxidant defense mechanisms is a virulence factor of this fungus. To test this hypothesis, we are studying two pathways important in resistance to hydrogen peroxide. One pathway involves alternative oxidase, which is a mitochondrial inner membrane enzyme. The other pathway involves two differentially expressed catalase genes. The alternative oxidase gene AOX I and one of the two catalase genes, CATA, are induced by hydrogen peroxide. The second catalase gene, CATB, is constitutively expressed but appears to make both cell-associated and secreted isoforms of catalase. Analysis of the gene regulatory mechanisms of AOX I and CATA will lead to identification of global regulatory circuits and signal transduction pathways that are activated upon exposure to oxidative stress. We hypothesize that such regulatory pathways will be activated in H. capsulatum during infection of mammalian hosts, and that additional virulence genes will be found to be members of the same regulon(s) as AOXI and CATA. In addition, work is underway to create H. capsulatum mutants deficient in the alternative oxidase and each of the catalase enzymes. Such mutants will be useful in direct tests of the role of these enzymes in pathogenesis. References Johnson, C.H., Prigge, J.T., Warren, A.D., McEwen, J.E. Characterization of an alternative oxidase activity of Histoplasma capsulatum. Yeast. 2003 Apr 15;20(5):381-8. J ohnson, C.H., Klotz, M.G., York, J.L., Kruft, V. and McEwen, J.E. Redundancy, phylogeny and differential expression of Histoplasma capsulatum catalases. Microbiology 148: 1129-1142, 2002. Marathe, S.V., and McEwen, J.E. Expression of the divergent transcription unit containing the yeast PET122 and OXA1 genes. Bioch. And Mol. Biol. Int. 47: 971-977, 1999. Johnson, C.H., and McEwen, J.E. Isolation of a Histoplasma capsulatum cDNA that complements a mitochondrial NAD(+)-isocitrate dehydrogenase subunit I-deficient mutant of Saccharomyces cerevisiae . Yeast 15: 799-804, 1999. Manthey, G.M., Przybyla-Zawislak, B.D., and McEwen, J.E. The Saccharomyces cerevisiae Pet309 protein is embedded in the mitochondrial inner membrane. Eur. J. Bioch. 255: 156-161, 1998. Johnson, C.H., and McEwen, J.E.. Mitochondrial protein synthesis is not required for efficient excision of intron aI5b from COX1 pre-mRNA in Saccharomyces cerevisiae . Mol. Gen. Genet. 256: 88-91, 1997
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