Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>

ABSTRACT Glucose transporters are important for viability and infectivity of the disease-causing amastigote stages of Leishmania mexicana. The Δgt1-3 null mutant, in which the 3 clustered glucose transporter genes, GT1, GT2, and GT3, have been deleted, is strongly impaired in growth inside macrophag...

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Autores principales:	Xiuhong Feng, Khoa D. Tran, Marco A. Sanchez, Hakima Al Mezewghi, Scott M. Landfear
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Leishmania endoplasmic reticulum gene knockouts glucose transporter suppressor virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3fe2dc0410634cc6989be263dd42631a
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spelling	oai:doaj.org-article:3fe2dc0410634cc6989be263dd42631a2021-11-15T15:25:50ZGlucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>10.1128/mSphere.00349-182379-5042https://doaj.org/article/3fe2dc0410634cc6989be263dd42631a2018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00349-18https://doaj.org/toc/2379-5042ABSTRACT Glucose transporters are important for viability and infectivity of the disease-causing amastigote stages of Leishmania mexicana. The Δgt1-3 null mutant, in which the 3 clustered glucose transporter genes, GT1, GT2, and GT3, have been deleted, is strongly impaired in growth inside macrophages in vitro. We have now demonstrated that this null mutant is also impaired in virulence in the BALB/c murine model of infection and forms lesions considerably more slowly than wild-type parasites. Previously, we established that amplification of the PIFTC3 gene, which encodes an intraflagellar transport protein, both facilitated and accompanied the isolation of the original Δgt1-3 null mutant generated in extracellular insect-stage promastigotes. We have now isolated Δgt1-3 null mutants without coamplification of PIFTC3. These amplicon-negative null mutants are further impaired in growth as promastigotes, compared to the previously described null mutants containing the PIFTC3 amplification. In contrast, the GT3 glucose transporter plays an especially important role in promoting amastigote viability. A line that expresses only the single glucose transporter GT3 grows as well inside macrophages and induces lesions in animals as robustly as do wild-type amastigotes, but lines expressing only the GT1 or GT2 transporters replicate poorly in macrophages. Strikingly, GT3 is restricted largely to the endoplasmic reticulum in intracellular amastigotes. This observation raises the possibility that GT3 may play an important role as an intracellular glucose transporter in the infectious stage of the parasite life cycle. IMPORTANCE Glucose transport plays important roles for in vitro growth of insect-stage promastigotes and especially for viability of intramacrophage mammalian host-stage amastigotes of Leishmania mexicana. However, the roles of the three distinct glucose transporters, GT1, GT2, and GT3, in parasite viability inside macrophages and virulence in mice have not been fully explored. Parasite lines expressing GT1 or GT2 alone were strongly impaired in growth inside macrophages, but lines expressing GT3 alone infected macrophages and caused lesions in mice as robustly as wild-type parasites. Notably, GT3 localizes to the endoplasmic reticulum of intracellular amastigotes, suggesting a potential role for salvage of glucose from that organelle for viability of infectious amastigotes. This study establishes the unique role of GT3 for parasite survival inside host macrophages and for robust virulence in infected animals.Xiuhong FengKhoa D. TranMarco A. SanchezHakima Al MezewghiScott M. LandfearAmerican Society for MicrobiologyarticleLeishmaniaendoplasmic reticulumgene knockoutsglucose transportersuppressorvirulenceMicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Leishmania endoplasmic reticulum gene knockouts glucose transporter suppressor virulence Microbiology QR1-502
spellingShingle	Leishmania endoplasmic reticulum gene knockouts glucose transporter suppressor virulence Microbiology QR1-502 Xiuhong Feng Khoa D. Tran Marco A. Sanchez Hakima Al Mezewghi Scott M. Landfear Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
description	ABSTRACT Glucose transporters are important for viability and infectivity of the disease-causing amastigote stages of Leishmania mexicana. The Δgt1-3 null mutant, in which the 3 clustered glucose transporter genes, GT1, GT2, and GT3, have been deleted, is strongly impaired in growth inside macrophages in vitro. We have now demonstrated that this null mutant is also impaired in virulence in the BALB/c murine model of infection and forms lesions considerably more slowly than wild-type parasites. Previously, we established that amplification of the PIFTC3 gene, which encodes an intraflagellar transport protein, both facilitated and accompanied the isolation of the original Δgt1-3 null mutant generated in extracellular insect-stage promastigotes. We have now isolated Δgt1-3 null mutants without coamplification of PIFTC3. These amplicon-negative null mutants are further impaired in growth as promastigotes, compared to the previously described null mutants containing the PIFTC3 amplification. In contrast, the GT3 glucose transporter plays an especially important role in promoting amastigote viability. A line that expresses only the single glucose transporter GT3 grows as well inside macrophages and induces lesions in animals as robustly as do wild-type amastigotes, but lines expressing only the GT1 or GT2 transporters replicate poorly in macrophages. Strikingly, GT3 is restricted largely to the endoplasmic reticulum in intracellular amastigotes. This observation raises the possibility that GT3 may play an important role as an intracellular glucose transporter in the infectious stage of the parasite life cycle. IMPORTANCE Glucose transport plays important roles for in vitro growth of insect-stage promastigotes and especially for viability of intramacrophage mammalian host-stage amastigotes of Leishmania mexicana. However, the roles of the three distinct glucose transporters, GT1, GT2, and GT3, in parasite viability inside macrophages and virulence in mice have not been fully explored. Parasite lines expressing GT1 or GT2 alone were strongly impaired in growth inside macrophages, but lines expressing GT3 alone infected macrophages and caused lesions in mice as robustly as wild-type parasites. Notably, GT3 localizes to the endoplasmic reticulum of intracellular amastigotes, suggesting a potential role for salvage of glucose from that organelle for viability of infectious amastigotes. This study establishes the unique role of GT3 for parasite survival inside host macrophages and for robust virulence in infected animals.
format	article
author	Xiuhong Feng Khoa D. Tran Marco A. Sanchez Hakima Al Mezewghi Scott M. Landfear
author_facet	Xiuhong Feng Khoa D. Tran Marco A. Sanchez Hakima Al Mezewghi Scott M. Landfear
author_sort	Xiuhong Feng
title	Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
title_short	Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
title_full	Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
title_fullStr	Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
title_full_unstemmed	Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>
title_sort	glucose transporters and virulence in <italic toggle="yes">leishmania mexicana</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/3fe2dc0410634cc6989be263dd42631a
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Glucose Transporters and Virulence in <italic toggle="yes">Leishmania mexicana</italic>

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