title: Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis.
abstract: The fungal pathogen Histoplasma capsulatum causes respiratory and disseminated disease, even in immunocompetent hosts. In contrast to opportunistic pathogens, which are readily controlled by phagocytic cells, H. capsulatum yeasts are able to infect macrophages, survive antimicrobial defenses, and proliferate as an intracellular pathogen. In this review, we discuss some of the molecular mechanisms that enable H. capsulatum yeasts to overcome obstacles to intracellular pathogenesis. H. capsulatum yeasts gain refuge from extracellular obstacles such as antimicrobial lung surfactant proteins by engaging the β-integrin family of phagocytic receptors to promote entry into macrophages. In addition, H. capsulatum yeasts conceal immunostimulatory β-glucans to avoid triggering signaling receptors such as the β-glucan receptor Dectin-1. H. capsulatum yeasts counteract phagocyte-produced reactive oxygen species by expression of oxidative stress defense enzymes including an extracellular superoxide dismutase and an extracellular catalase. Within the phagosome, H. capsulatum yeasts block phagosome acidification, acquire essential metals such as iron and zinc, and utilize de novo biosynthesis pathways to overcome nutritional limitations. These mechanisms explain how H. capsulatum yeasts avoid and negate macrophage defense strategies and establish a hospitable intracellular niche, making H. capsulatum a successful intracellular pathogen of macrophages.
authors.affiliation: Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Garfoot
authors.affiliation: Department of Microbiology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Rappleye
mesh_terms: D002374:Catalase / Q000378:metabolism; D006658:Histoplasma / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase
keywords: CR3; Dectin-1; ROS; cell wall; fungal pathogenesis; glucan; iron; phagosome; zinc