Differentiation of the fungus Histoplasma capsulatum into a pathogen of phagocytes

Abstract

Mammalian body temperature triggers differentiation of the fungal pathogen Histoplasma capsulatum into yeast cells. The Drk1 regulatory kinase and an interdependent network of Ryp transcription factors establish the yeast state. Beyond morphology, the differentiation-dependent expression program equips yeasts for invasion and survival within phagosomes. Yeast cells produce α-glucan and the Eng1 endoglucanase which hide yeasts from immune detection. Secretion of yeast phase-specific Sod3 and CatB detoxify phagocyte-derived reactive oxygen molecules. Histoplasma cells adapt to iron and zinc limitation in activated macrophages by production of siderophores and the Zrt2 transporter, respectively. Yeasts also respond to inflammation-associated hypoxia. Histoplasma pathogenicity thus relies on factors controlled by yeast differentiation as well as environment-dependent responses.

Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion

“…These changes in the fungal cell surface have profound effects on how the invading pathogen is perceived by the innate immune system. For instance, growth in the host triggers differentiation of Histoplasma capsulatum and stimulates deposition of the immunologically silent polysaccharide α-glucan on top of inflammatory β-glucan, thereby limiting inflammatory immune responses [54, 72]. Three recent studies in C. albicans now shed light on other ways in which fungal adaptation to the host niche influences the innate immune response.…”

Flying under the radar: Histoplasma capsulatum avoidance of innate immune recognition

“…Simultaneously, H. capsulatum obscures itself from immune signaling receptors like Dectin-1 by masking its immunostimulatory β-glucans with a non-stimulatory α-(1,3)glucan layer and by trimming extraneous β-glucan with secreted endonucleases. Once it has achieved internalization, other virulence factors of H. capsulatum transform the macrophage phagolysosome into a safe environment for proliferation, thereby isolating the yeast from detection by other immune cells [73]. Host phagocytes express a variety of receptors which are capable of recognizing H. capsulatum yeasts.…”

How Environmental Fungi Cause a Range of Clinical Outcomes in Susceptible Hosts

“…As dendritic cells are much better at killing and processing Histoplasma yeast for antigen presentation [341], localization of Hsp60 to the cell surface may represent a targeted means for Histoplasma yeast to enter their macrophage safe havens [342]. Additional traits important for survival in phagolysosomes, such as acquisition of the limiting nutrients iron and zinc, are reviewed elsewhere [343,344].…”