Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting

ABSTRACT Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen Toxopla...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Arun Kumar Haldar, Utsav Nigam, Masahiro Yamamoto, Jörn Coers, Neena Goyal
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Leishmania nonphagocytic cells guanylate binding proteins GBP GTPases IRGM Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c7f263c1d4714a65b0e4676566ce3749
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c7f263c1d4714a65b0e4676566ce3749
record_format	dspace
spelling	oai:doaj.org-article:c7f263c1d4714a65b0e4676566ce37492021-11-15T15:56:43ZGuanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting10.1128/mBio.01464-202150-7511https://doaj.org/article/c7f263c1d4714a65b0e4676566ce37492020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01464-20https://doaj.org/toc/2150-7511ABSTRACT Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen Toxoplasma and facilitate PV disruption and lytic parasite killing. While the GBP defense program targeting Toxoplasma has been studied in some detail, the role of GBPs in host defense to other protozoan pathogens is poorly characterized. Here, we report a critical role for both mouse and human GBPs in the cell-autonomous immune response against the vector-borne parasite Leishmania donovani. Although L. donovani can infect both phagocytic and nonphagocytic cells, it predominantly replicates inside professional phagocytes. The underlying basis for this cell type tropism is unclear. Here, we demonstrate that GBPs restrict growth of L. donovani in both mouse and human nonphagocytic cells. GBP-mediated restriction of L. donovani replication occurs via a noncanonical pathway that operates independent of detectable translocation of GBPs to L. donovan-containing vacuoles (LCVs). Instead of promoting the lytic destruction of PVs, as reported for GBP-mediated killing of Toxoplasma in phagocytic cells, GBPs facilitate the delivery of L. donovani into autolysosomal-marker-positive compartments in mouse embryonic fibroblasts as well as the human epithelial cell line A549. Together our results show that GBPs control a novel cell-autonomous host defense program, which renders nonphagocytic cells nonpermissible for efficient Leishmania replication. IMPORTANCE The obligate intracellular parasite Leishmania causes the disease leishmaniasis, which is transmitted to mammalian hosts, including humans, via the sandfly vector. Following the bite-induced breach of the skin barrier, Leishmania is known to live and replicate predominantly inside professional phagocytes. Although Leishmania is also able to infect nonphagocytic cells, nonphagocytic cells support limited parasitic replication for unknown reasons. In this study, we show that nonphagocytic cells possess an intrinsic property to restrict Leishmania growth. Our study defines a novel role for a family of host defense proteins, the guanylate binding proteins (GBPs), in antileishmanial immunity. Mechanistically, our data indicate that GBPs facilitate the delivery of Leishmania into antimicrobial autolysosomes, thereby enhancing parasite clearance in nonphagocytic cells. We propose that this GBP-dependent host defense program makes nonphagocytic cells an inhospitable host cell type for Leishmania growth.Arun Kumar HaldarUtsav NigamMasahiro YamamotoJörn CoersNeena GoyalAmerican Society for MicrobiologyarticleLeishmanianonphagocytic cellsguanylate binding proteinsGBPGTPasesIRGMMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Leishmania nonphagocytic cells guanylate binding proteins GBP GTPases IRGM Microbiology QR1-502
spellingShingle	Leishmania nonphagocytic cells guanylate binding proteins GBP GTPases IRGM Microbiology QR1-502 Arun Kumar Haldar Utsav Nigam Masahiro Yamamoto Jörn Coers Neena Goyal Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
description	ABSTRACT Interferon (IFN)-inducible guanylate binding proteins (GBPs) play important roles in host defense against many intracellular pathogens that reside within pathogen-containing vacuoles (PVs). For instance, members of the GBP family translocate to PVs occupied by the protozoan pathogen Toxoplasma and facilitate PV disruption and lytic parasite killing. While the GBP defense program targeting Toxoplasma has been studied in some detail, the role of GBPs in host defense to other protozoan pathogens is poorly characterized. Here, we report a critical role for both mouse and human GBPs in the cell-autonomous immune response against the vector-borne parasite Leishmania donovani. Although L. donovani can infect both phagocytic and nonphagocytic cells, it predominantly replicates inside professional phagocytes. The underlying basis for this cell type tropism is unclear. Here, we demonstrate that GBPs restrict growth of L. donovani in both mouse and human nonphagocytic cells. GBP-mediated restriction of L. donovani replication occurs via a noncanonical pathway that operates independent of detectable translocation of GBPs to L. donovan-containing vacuoles (LCVs). Instead of promoting the lytic destruction of PVs, as reported for GBP-mediated killing of Toxoplasma in phagocytic cells, GBPs facilitate the delivery of L. donovani into autolysosomal-marker-positive compartments in mouse embryonic fibroblasts as well as the human epithelial cell line A549. Together our results show that GBPs control a novel cell-autonomous host defense program, which renders nonphagocytic cells nonpermissible for efficient Leishmania replication. IMPORTANCE The obligate intracellular parasite Leishmania causes the disease leishmaniasis, which is transmitted to mammalian hosts, including humans, via the sandfly vector. Following the bite-induced breach of the skin barrier, Leishmania is known to live and replicate predominantly inside professional phagocytes. Although Leishmania is also able to infect nonphagocytic cells, nonphagocytic cells support limited parasitic replication for unknown reasons. In this study, we show that nonphagocytic cells possess an intrinsic property to restrict Leishmania growth. Our study defines a novel role for a family of host defense proteins, the guanylate binding proteins (GBPs), in antileishmanial immunity. Mechanistically, our data indicate that GBPs facilitate the delivery of Leishmania into antimicrobial autolysosomes, thereby enhancing parasite clearance in nonphagocytic cells. We propose that this GBP-dependent host defense program makes nonphagocytic cells an inhospitable host cell type for Leishmania growth.
format	article
author	Arun Kumar Haldar Utsav Nigam Masahiro Yamamoto Jörn Coers Neena Goyal
author_facet	Arun Kumar Haldar Utsav Nigam Masahiro Yamamoto Jörn Coers Neena Goyal
author_sort	Arun Kumar Haldar
title	Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
title_short	Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
title_full	Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
title_fullStr	Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
title_full_unstemmed	Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting
title_sort	guanylate binding proteins restrict <named-content content-type="genus-species">leishmania donovani</named-content> growth in nonphagocytic cells independent of parasitophorous vacuolar targeting
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c7f263c1d4714a65b0e4676566ce3749
work_keys_str_mv	AT arunkumarhaldar guanylatebindingproteinsrestrictnamedcontentcontenttypegenusspeciesleishmaniadonovaninamedcontentgrowthinnonphagocyticcellsindependentofparasitophorousvacuolartargeting AT utsavnigam guanylatebindingproteinsrestrictnamedcontentcontenttypegenusspeciesleishmaniadonovaninamedcontentgrowthinnonphagocyticcellsindependentofparasitophorousvacuolartargeting AT masahiroyamamoto guanylatebindingproteinsrestrictnamedcontentcontenttypegenusspeciesleishmaniadonovaninamedcontentgrowthinnonphagocyticcellsindependentofparasitophorousvacuolartargeting AT jorncoers guanylatebindingproteinsrestrictnamedcontentcontenttypegenusspeciesleishmaniadonovaninamedcontentgrowthinnonphagocyticcellsindependentofparasitophorousvacuolartargeting AT neenagoyal guanylatebindingproteinsrestrictnamedcontentcontenttypegenusspeciesleishmaniadonovaninamedcontentgrowthinnonphagocyticcellsindependentofparasitophorousvacuolartargeting
_version_	1718427119392915456

Guanylate Binding Proteins Restrict <named-content content-type="genus-species">Leishmania donovani</named-content> Growth in Nonphagocytic Cells Independent of Parasitophorous Vacuolar Targeting

Ejemplares similares