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Discovery Of Intracellular Growth Requirements of the Fungal Pathogen Histoplasma capsulatum

Zemska, Olga

Abstract Details

2012, Master of Science, Ohio State University, Microbiology.

Histoplasma capsulatum is a pathogenic fungus endemic to the Ohio and Mississippi River valleys. Infection of mammals by Histoplasma causes respiratory histoplasmosis of varying severity which can lead to disseminated life-threatening disease. Upon inhalation into the mammalian lung, Histoplasma yeast are taken up by alveolar macrophages in which they replicate and ultimately lyse the host immune cells. Histoplasma’s virulence in these phagocytes and the inability of the immune system to control the infection highlights the need to understand the mechanisms underlying the pathogenicity of this fungus.

We sought to identify Histoplasma genes required for survival and growth in macrophages. We optimized procedures for Agrobacterium-mediated transformation of Histoplasma to facilitate insertional mutagenesis, and developed a simple and efficient screen for Histoplasma mutants unable to lyse host macrophages. We identified 14 mutants from 6500 that had decreased virulence in phagocytes. One of the loci identified is a heat shock protein 90 homolog (HSP82) which we show is instrumental for Histoplasma yeast to adapt to infection-associated stresses. A second identified locus, a riboflavin biosynthesis enzyme (RIB2), indicates that de novo vitamin biosynthesis is required for fungal proliferation within host cells. Murine infections with these mutants confirm each is necessary for full Histoplasma virulence in mammalian hosts. The attenuation of the rib2::T-DNA mutant suggests that the mammalian phagosome is a vitamin-limiting environment. Using folate biosynthesis inhibitors to arrest intracellular Histoplasma growth, we show that Histoplasma also requires de novo synthesis of folate intermediates. Together, these data demonstrate that de novo vitamin biosynthesis enables Histoplasma yeast to replicate in the nutrient-limiting macrophage phagosome and highlights vitamin biosynthetic pathways as potential therapeutic targets for treatment of histoplasmosis.

Chad Rappleye (Committee Chair)
Birgit Alber (Committee Member)
Charles Daniels (Committee Member)
Daniel Wozniak (Committee Member)
121 p.

Recommended Citations

Citations

  • Zemska, O. (2012). Discovery Of Intracellular Growth Requirements of the Fungal Pathogen Histoplasma capsulatum [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343803044

    APA Style (7th edition)

  • Zemska, Olga. Discovery Of Intracellular Growth Requirements of the Fungal Pathogen Histoplasma capsulatum. 2012. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1343803044.

    MLA Style (8th edition)

  • Zemska, Olga. "Discovery Of Intracellular Growth Requirements of the Fungal Pathogen Histoplasma capsulatum." Master's thesis, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343803044

    Chicago Manual of Style (17th edition)