Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis. (25th November 2015)

• Record Type: Journal Article
• Authors: Garfoot, Andrew L.; Rappleye, Chad A.
• Is Part Of: FEBS journal. Volume 283:Number 4(2016)
• Page Start: 619
• Page End: 633
• Publication Date: 2015-11-25
• Subjects: cell wall -- CR3 -- Dectin‐1 -- fungal pathogenesis -- glucan -- iron -- phagosome -- ROS -- zinc; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13389
• Languages: English
• ISSNs: 1742-464X

Abstract

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. Abstract : This review highlights the challenges to intracellular pathogenesis and the molecular mechanisms that enable the fungal pathogen Histoplasma capsulatum to meet these obstacles. H. capsulatum promotes phagocytic uptake while limiting its detection by macrophages. Factors secreted by H. capsulatum yeasts neutralize antimicrobial defenses. Within the phagosome, yeasts express strategies to deal with limited nutrient availability and sequestration of essential metals.