Molecular mechanisms of Histoplasma pathogenesis

Abstract

Histoplasma capsulatum is a thermally dimorphic fungus that causes respiratory and systemic disease in both immunocompromised and immunocompetent individuals. Mammalian body temperatures trigger differentiation of Histoplasma into pathogenic yeasts, which infect and survive within host phagocytes. A signaling histidine kinase and three transcription factors regulate the dimorphic switch and expression of the yeast-phase regulon. Factors uniquely produced by yeasts facilitate Histoplasma survival by concealing molecular signatures to prevent Histoplasma detection by phagocytes and by detoxifying antimicrobial defense molecules produced by phagocytes. The synthesis of a-linked cell wall glucan polysaccharides enables stealthy entry into phagocytes and the expression of an extracellular superoxide dismutase and an extracellular catalase that protect Histoplasma yeasts specifically from host-derived reactive oxygen. Once survival and intracellular residence is accomplished, Histoplasma synthesizes factors for nutrient acquisition in the nutrient-limited phagosome, including iron-scavenging siderophores and a ferric reductase. In addition, Histoplasma yeasts secrete several novel factors with undefined functions that are probably linked to pathogenesis by virtue of their pathogenic-phase-specific expression and their extracellular location, which enables them to act at the host-pathogen interface.