Histoplasma mechanisms of pathogenesis - one portfolio doesn't fit all

Abstract

Histoplasma capsulatum is the leading cause of endemic mycosis in the world. Analyses of clinical isolates from different endemic regions show important diversity within the species. Recent molecular studies of two isolates, the Chemotype I NAm2 strain G217B and the Chemotype II Panamanian strain G186A, reveal significant genetic, structural, and molecular differences between these representative Histoplasma strains. Some of these variations have functional consequences, representing distinct molecular mechanisms that facilitate Histoplasma pathogenesis. The realization of Histoplasma strain diversity highlights the importance of characterizing Histoplasma virulence factors in the context of specific clinical strain isolates.

Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

“…Antifungal susceptibility testing of the isolates showed similar susceptibility profiles for fungicidal amphotericin B. NAm1, LAm, and the Panama isolates had slightly increased natural resistance to fluconazole compared with the NAm2 isolates, but all were still below the fluconazole breakpoints defined for Candida yeasts (40,41). Yeasts from the LAm and Panama, but not the NAm2, phylogenetic groups are characterized by cell walls that have ␣-glucan polysaccharides in addition to the ␤-glucan polysaccharide (42)(43)(44)(45)(46), and these isolates showed increased resistance to caspofungin compared to the resistance of NAm2 isolates. This correlation between ␣-glucan and less sensitivity to ␤-glucan synthase inhibitors is intriguing, yet the mechanism remains undefined at this point.…”

The cryptic sexual strategies of human fungal pathogens

“…H. capsulatum is closely related to Coccidioides and is ubiquitous in the soil where it generates asexual microconidia that, when inhaled, cause histoplasmosis 145 . The sexual cycle of this ascomycete was defined decades ago and mating types (designated as + and − ) are found at equal ratios in the environment, supportive of a sexual cycle 146,147 .…”

Histoplasma Capsulatum , Lung Infection and Immunity

“…Most isolates of H. capsulatum have both α- and β-glucan in their cell walls, but isolates from the North American 2 clade lack α-glucan [9]. While α-glucan − strains account for the majority of infections in immunocompetent individuals in North America, α-glucan + infections are associated with HIV [10]. In mouse models α-glucan − yeast causes more severe disease than α-glucan + , but only at high infectious inocula [11].…”

“…Despite infection usually being a ‘dead end’ for fungal replication, H. capsulatum appears specifically adapted to mammalian hosts. The transformation from mycelial to yeast phase at 37°C is crucial for infection; strains lacking this ability are avirulent [10]. The yeast is equipped for evading intracellular killing by phagocytes, with mechanisms to degrade reactive oxygen species (ROS), regulate lysosomal pH and capture essential nutrients that might otherwise be deprived [12–15].…”