Analysis of Hypoxia Response Mechanisms in Histoplasma capsulatum
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Date
2014-05
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Publisher
The Ohio State University
Abstract
Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the Ohio River valley. This pathogen is particularly harmful because of its ability to cause disease in both immunocompromised and immunocompetent hosts. Histoplasma primarily affects the respiratory system, leading to colonization of the lungs, but can disseminate to other organs such as the spleen and bone marrow. The mechanisms of Histoplasma virulence and how it adapts to growth within host cells and the host environment are relatively unknown. We have isolated a strain of H. capsulatum with a mutation in the DSC2 gene, which is postulated to regulate the fungal response to hypoxia. The Dsc complex responds to decreased sterol synthesis, which is coupled to decreased oxygen levels. We hypothesize that the Dsc complex may allow Histoplasma to survive in the potential hypoxic environments of different organs. To test this, we developed a complemented strain and analyzed the ability of the wild-type, the dsc2 mutant, and complemented strains to grow under low oxygen, conditions that mimic hypoxia in vitro (e.g., growth with CoCl2), and infection of cultured macrophages. The data obtained showed some indication of decreased survival of the dsc2 mutant in comparison with the wild-type and complemented strains. We also examined the progression of disease of the dsc2 mutant strain in vivo using a murine model of respiratory and disseminated histoplasmosis. A better understanding of Histoplasma virulence mechanisms such as the response to hypoxia could help to indicate new targets for potential therapeutics for histoplasmosis.
Description
Natural and Mathematical Sciences Poster Forum
Keywords
DSC2, Histoplasma, hypoxia, fungal infection, SRB1