O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures
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 replicati...
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2018-01-01
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doaj-2069720a83b749f9b77cc0d412a092fb2021-07-02T01:04:57ZengAmerican Society for MicrobiologymBio2150-75112018-01-0191e02121-1710.1128/mBio.02121-17O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body TemperaturesAndrew L. GarfootKristie D. GoughenourMarcel WuthrichMurugesan V. S. RajaramLarry S. SchlesingerBruce S. KleinChad A. RappleyeJ. Andrew AlspaughThe 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 β-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.http://mbio.asm.org/cgi/content/full/9/1/e02121-17 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrew L. Garfoot Kristie D. Goughenour Marcel Wuthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye J. Andrew Alspaugh |
spellingShingle |
Andrew L. Garfoot Kristie D. Goughenour Marcel Wuthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye J. Andrew Alspaugh O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures mBio |
author_facet |
Andrew L. Garfoot Kristie D. Goughenour Marcel Wuthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye J. Andrew Alspaugh |
author_sort |
Andrew L. Garfoot |
title |
O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title_short |
O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title_full |
O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title_fullStr |
O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title_full_unstemmed |
O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title_sort |
o-mannosylation of proteins enables histoplasma yeast survival at mammalian body temperatures |
publisher |
American Society for Microbiology |
series |
mBio |
issn |
2150-7511 |
publishDate |
2018-01-01 |
description |
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 β-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. |
url |
http://mbio.asm.org/cgi/content/full/9/1/e02121-17 |
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