The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading

ABSTRACT Toxoplasma gondii uses unique secretory organelles called rhoptries to inject an array of effector proteins into the host cytoplasm that hijack host cell functions. We have discovered a novel rhoptry pseudokinase effector, ROP54, which is injected into the host cell upon invasion and traffi...

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Autores principales:	Elliot W. Kim, Santhosh M. Nadipuram, Ashley L. Tetlow, William D. Barshop, Philip T. Liu, James A. Wohlschlegel, Peter J. Bradley
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Toxoplasma gondii guanylate binding proteins immunity-related GTPases pseudokinase rhoptry virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f969dd0a7b064a0e898dc43410fb7afe
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spelling	oai:doaj.org-article:f969dd0a7b064a0e898dc43410fb7afe2021-11-15T15:21:23ZThe Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading10.1128/mSphere.00045-162379-5042https://doaj.org/article/f969dd0a7b064a0e898dc43410fb7afe2016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00045-16https://doaj.org/toc/2379-5042ABSTRACT Toxoplasma gondii uses unique secretory organelles called rhoptries to inject an array of effector proteins into the host cytoplasm that hijack host cell functions. We have discovered a novel rhoptry pseudokinase effector, ROP54, which is injected into the host cell upon invasion and traffics to the cytoplasmic face of the parasitophorous vacuole membrane (PVM). Disruption of ROP54 in a type II strain of T. gondii does not affect growth in vitro but results in a 100-fold decrease in virulence in vivo, suggesting that ROP54 modulates some aspect of the host immune response. We show that parasites lacking ROP54 are more susceptible to macrophage-dependent clearance, further suggesting that ROP54 is involved in evasion of innate immunity. To determine how ROP54 modulates parasite virulence, we examined the loading of two known innate immune effectors, immunity-related GTPase b6 (IRGb6) and guanylate binding protein 2 (GBP2), in wild-type and ∆rop54II mutant parasites. While no difference in IRGb6 loading was seen, we observed a substantial increase in GBP2 loading on the parasitophorous vacuole (PV) of ROP54-disrupted parasites. These results demonstrate that ROP54 is a novel rhoptry effector protein that promotes Toxoplasma infections by modulating GBP2 loading onto parasite-containing vacuoles. IMPORTANCE The interactions between intracellular microbes and their host cells can lead to the discovery of novel drug targets. During Toxoplasma infections, host cells express an array of immunity-related GTPases (IRGs) and guanylate binding proteins (GBPs) that load onto the parasite-containing vacuole to clear the parasite. To counter this mechanism, the parasite secretes effector proteins that traffic to the vacuole to disarm the immunity-related loading proteins and evade the immune response. While the interplay between host IRGs and Toxoplasma effector proteins is well understood, little is known about how Toxoplasma neutralizes the GBP response. We describe here a T. gondii pseudokinase effector, ROP54, that localizes to the vacuole upon invasion and is critical for parasite virulence. Toxoplasma vacuoles lacking ROP54 display an increased loading of the host immune factor GBP2, but not IRGb6, indicating that ROP54 plays a distinct role in immune evasion.Elliot W. KimSanthosh M. NadipuramAshley L. TetlowWilliam D. BarshopPhilip T. LiuJames A. WohlschlegelPeter J. BradleyAmerican Society for MicrobiologyarticleToxoplasma gondiiguanylate binding proteinsimmunity-related GTPasespseudokinaserhoptryvirulenceMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma gondii guanylate binding proteins immunity-related GTPases pseudokinase rhoptry virulence Microbiology QR1-502
spellingShingle	Toxoplasma gondii guanylate binding proteins immunity-related GTPases pseudokinase rhoptry virulence Microbiology QR1-502 Elliot W. Kim Santhosh M. Nadipuram Ashley L. Tetlow William D. Barshop Philip T. Liu James A. Wohlschlegel Peter J. Bradley The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
description	ABSTRACT Toxoplasma gondii uses unique secretory organelles called rhoptries to inject an array of effector proteins into the host cytoplasm that hijack host cell functions. We have discovered a novel rhoptry pseudokinase effector, ROP54, which is injected into the host cell upon invasion and traffics to the cytoplasmic face of the parasitophorous vacuole membrane (PVM). Disruption of ROP54 in a type II strain of T. gondii does not affect growth in vitro but results in a 100-fold decrease in virulence in vivo, suggesting that ROP54 modulates some aspect of the host immune response. We show that parasites lacking ROP54 are more susceptible to macrophage-dependent clearance, further suggesting that ROP54 is involved in evasion of innate immunity. To determine how ROP54 modulates parasite virulence, we examined the loading of two known innate immune effectors, immunity-related GTPase b6 (IRGb6) and guanylate binding protein 2 (GBP2), in wild-type and ∆rop54II mutant parasites. While no difference in IRGb6 loading was seen, we observed a substantial increase in GBP2 loading on the parasitophorous vacuole (PV) of ROP54-disrupted parasites. These results demonstrate that ROP54 is a novel rhoptry effector protein that promotes Toxoplasma infections by modulating GBP2 loading onto parasite-containing vacuoles. IMPORTANCE The interactions between intracellular microbes and their host cells can lead to the discovery of novel drug targets. During Toxoplasma infections, host cells express an array of immunity-related GTPases (IRGs) and guanylate binding proteins (GBPs) that load onto the parasite-containing vacuole to clear the parasite. To counter this mechanism, the parasite secretes effector proteins that traffic to the vacuole to disarm the immunity-related loading proteins and evade the immune response. While the interplay between host IRGs and Toxoplasma effector proteins is well understood, little is known about how Toxoplasma neutralizes the GBP response. We describe here a T. gondii pseudokinase effector, ROP54, that localizes to the vacuole upon invasion and is critical for parasite virulence. Toxoplasma vacuoles lacking ROP54 display an increased loading of the host immune factor GBP2, but not IRGb6, indicating that ROP54 plays a distinct role in immune evasion.
format	article
author	Elliot W. Kim Santhosh M. Nadipuram Ashley L. Tetlow William D. Barshop Philip T. Liu James A. Wohlschlegel Peter J. Bradley
author_facet	Elliot W. Kim Santhosh M. Nadipuram Ashley L. Tetlow William D. Barshop Philip T. Liu James A. Wohlschlegel Peter J. Bradley
author_sort	Elliot W. Kim
title	The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
title_short	The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
title_full	The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
title_fullStr	The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
title_full_unstemmed	The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading
title_sort	rhoptry pseudokinase rop54 modulates <named-content content-type="genus-species">toxoplasma gondii</named-content> virulence and host gbp2 loading
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/f969dd0a7b064a0e898dc43410fb7afe
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The Rhoptry Pseudokinase ROP54 Modulates <named-content content-type="genus-species">Toxoplasma gondii</named-content> Virulence and Host GBP2 Loading

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