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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750402/ https://www.ncbi.nlm.nih.gov/pubmed/29295913 http://dx.doi.org/10.1128/mBio.02121-17 |
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author | Garfoot, Andrew L. Goughenour, Kristie D. Wüthrich, Marcel Rajaram, Murugesan V. S. Schlesinger, Larry S. Klein, Bruce S. Rappleye, Chad A. |
author_facet | Garfoot, Andrew L. Goughenour, Kristie D. Wüthrich, Marcel Rajaram, Murugesan V. S. Schlesinger, Larry S. Klein, Bruce S. Rappleye, Chad A. |
author_sort | Garfoot, Andrew L. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-5750402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-57504022018-01-03 O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures Garfoot, Andrew L. Goughenour, Kristie D. Wüthrich, Marcel Rajaram, Murugesan V. S. Schlesinger, Larry S. Klein, Bruce S. Rappleye, Chad A. mBio Research Article 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. American Society for Microbiology 2018-01-02 /pmc/articles/PMC5750402/ /pubmed/29295913 http://dx.doi.org/10.1128/mBio.02121-17 Text en Copyright © 2018 Garfoot et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Garfoot, Andrew L. Goughenour, Kristie D. Wüthrich, Marcel Rajaram, Murugesan V. S. Schlesinger, Larry S. Klein, Bruce S. Rappleye, Chad A. O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750402/ https://www.ncbi.nlm.nih.gov/pubmed/29295913 http://dx.doi.org/10.1128/mBio.02121-17 |
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