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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Andrew L. Garfoot, Kristie D. Goughenour, Marcel Wüthrich, Murugesan V. S. Rajaram, Larry S. Schlesinger, Bruce S. Klein, Chad A. Rappleye
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Histoplasma glycosylation mannose phagocyte thermotolerance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5c09d23e88e94f35870097fd644ba235
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5c09d23e88e94f35870097fd644ba235
record_format	dspace
spelling	oai:doaj.org-article:5c09d23e88e94f35870097fd644ba2352021-11-15T15:53:25ZO-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures10.1128/mBio.02121-172150-7511https://doaj.org/article/5c09d23e88e94f35870097fd644ba2352018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02121-17https://doaj.org/toc/2150-7511ABSTRACT 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.Andrew L. GarfootKristie D. GoughenourMarcel WüthrichMurugesan V. S. RajaramLarry S. SchlesingerBruce S. KleinChad A. RappleyeAmerican Society for MicrobiologyarticleHistoplasmaglycosylationmannosephagocytethermotoleranceMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Histoplasma glycosylation mannose phagocyte thermotolerance Microbiology QR1-502
spellingShingle	Histoplasma glycosylation mannose phagocyte thermotolerance Microbiology QR1-502 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
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.
format	article
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
title	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_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_sort	o-mannosylation of proteins enables <italic toggle="yes">histoplasma</italic> yeast survival at mammalian body temperatures
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/5c09d23e88e94f35870097fd644ba235
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
_version_	1718427277947043840

O-Mannosylation of Proteins Enables <italic toggle="yes">Histoplasma</italic> Yeast Survival at Mammalian Body Temperatures

Ejemplares similares