O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures

Abstract

The ability to grow at mammalian body temperatures is critical for pathogen infection of humans. For the thermally dimorphic fungal pathogen Histoplasma capsulatum, elevated temperature is required for differentiation of mycelia or conidia into yeast cells, a step critical for invasion and replication within phagocytic immune cells. Posttranslational glycosylation of extracellular proteins characterizes factors produced by the pathogenic yeast cells but not those of avirulent mycelia, correlating glycosylation with infection. Histoplasma yeast cells lacking the Pmt1 and Pmt2 protein mannosyltransferases, which catalyze O-linked mannosylation of proteins, are severely attenuated during infection of mammalian hosts. Cells lacking Pmt2 have altered surface characteristics that increase recognition of yeast cells by the macrophage mannose receptor and reduce recognition by the ␤-glucan receptor Dectin-1. Despite these changes, yeast cells lacking these factors still associate with and survive within phagocytes. Depletion of macrophages or neutrophils in vivo does not recover the virulence of the mutant yeast cells. We show that yeast cells lacking Pmt functions are more sensitive to thermal stress in vitro and consequently are unable to productively infect mice, even in the absence of fever. Treatment of mice with cyclophosphamide reduces the normal core body temperature of mice, and this decrease is sufficient to restore the infectivity of O-mannosylation-deficient yeast cells. These findings demonstrate that O-mannosylation of proteins increases the thermotolerance of Histoplasma yeast cells, which facilitates infection of mammalian hosts.IMPORTANCE For dimorphic fungal pathogens, mammalian body temperature can have contrasting roles. Mammalian body temperature induces differentiation of the fungal pathogen Histoplasma capsulatum into a pathogenic state characterized by infection of host phagocytes. On the other hand, elevated temperatures represent a significant barrier to infection by many microbes. By functionally characterizing cells lacking O-linked mannosylation enzymes, we show that protein mannosylation confers thermotolerance on H. capsulatum, enabling infection of mammalian hosts.

Thermotolerance of Histoplasma capsulatum at 40 °C predominates among clinical isolates from different Latin American regions

“… 7 , 9 , 20 , 21 In a few cases, these data were analyzed by overlooking important associations with critical aspects of the interaction between the fungus and its environment. Studies of H. capsulatum assessing thermosensitivity associated with fungal virulence were conducted by Medoff et al, 6 Keath et al, 22 Spitzer et al, 11 and Gargano et al 23 Recently, Garfoot et al 24 suggested that the thermotolerance of the Histoplasma Y-phase to the body temperature of the mammalian host is associated with the O-mannosylation of its proteins. However, most of these reports evaluated a scarce number of H. capsulatum isolates or strains that came from circumscribed geographic areas from North America, which are not representative of the genetic and phenotypic fungal changes that may be occurring in different regions associated with the phylogeographic distribution of the H. capsulatum complex in the Americas, as stated by Kasuga et al 13 and Teixeira et al 25 …”

Insights on Covid‐19 with superimposed pulmonary histoplasmosis: The possible nexus

“…Neutrophils and macrophages engulf H. capsulatum in the respiratory epithelium; some inhaled H. capsulatum is rapidly transported by lymphatics to the bloodstream to avoid their destruction by the immune cells 14 . Body temperature increases the differentiation of H. capsulatum into pathogenic yeast, which survives within the phagocytes 15 . Many intracellular signaling pathways, like histidine kinase, regulate yeast proliferation expression and immune cell recognition 16 .…”

Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

“…For fungal pathogens, glycans ( N - and O -linked) assemble on cell surface glycoproteins to regulate pathogen adhesion and interaction with host cells during infection [ 61 ]. The critical role of glycosylation in cell wall integrity, morphogenesis, virulence, and immune recognition has been reported in Candida spp., A. fumigatus , and Histoplasma capsulatum [ 62 , 63 , 64 , 65 ]. In a recent study, the importance of core N -glycan structure in relation to the virulence of C. neoformans was explored [ 48 ] ( Figure 3 B).…”