O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> 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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2018-03-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02121-17 |
| _version_ | 1818844410596556800 |
|---|---|
| author | Andrew L. Garfoot Kristie D. Goughenour Marcel Wüthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye |
| author_facet | Andrew L. Garfoot Kristie D. Goughenour Marcel Wüthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye |
| author_sort | Andrew L. Garfoot |
| collection | DOAJ |
| description | 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 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. 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. |
| first_indexed | 2024-12-19T05:13:19Z |
| format | Article |
| id | doaj.art-5c09d23e88e94f35870097fd644ba235 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T05:13:19Z |
| publishDate | 2018-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-5c09d23e88e94f35870097fd644ba2352022-12-21T20:34:44ZengAmerican Society for MicrobiologymBio2150-75112018-03-019110.1128/mBio.02121-17O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body TemperaturesAndrew L. Garfoot0Kristie D. Goughenour1Marcel Wüthrich2Murugesan V. S. Rajaram3Larry S. Schlesinger4Bruce S. Klein5Chad A. Rappleye6Department of Microbiology, Ohio State University, Columbus, Ohio, USADepartment of Microbiology, Ohio State University, Columbus, Ohio, USADepartment of Pediatrics, University of Wisconsin, Madison, Wisconsin, USADepartment of Microbial Infection and Immunity, Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, USADepartment of Microbial Infection and Immunity, Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, USADepartment of Pediatrics, University of Wisconsin, Madison, Wisconsin, USADepartment of Microbiology, Ohio State University, Columbus, Ohio, USAABSTRACT 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. 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.https://journals.asm.org/doi/10.1128/mBio.02121-17Histoplasmaglycosylationmannosephagocytethermotolerance |
| spellingShingle | Andrew L. Garfoot Kristie D. Goughenour Marcel Wüthrich Murugesan V. S. Rajaram Larry S. Schlesinger Bruce S. Klein Chad A. Rappleye O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures mBio Histoplasma glycosylation mannose phagocyte thermotolerance |
| title | O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures |
| title_full | O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures |
| title_fullStr | O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures |
| title_full_unstemmed | O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures |
| title_short | O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures |
| title_sort | o mannosylation of proteins enables italic toggle yes histoplasma italic yeast survival at mammalian body temperatures |
| topic | Histoplasma glycosylation mannose phagocyte thermotolerance |
| url | https://journals.asm.org/doi/10.1128/mBio.02121-17 |
| work_keys_str_mv | AT andrewlgarfoot omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT kristiedgoughenour omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT marcelwuthrich omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT murugesanvsrajaram omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT larrysschlesinger omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT brucesklein omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures AT chadarappleye omannosylationofproteinsenablesitalictoggleyeshistoplasmaitalicyeastsurvivalatmammalianbodytemperatures |