Unveiling the pathogen behind the vacuole

Liehl, Peter; Zuzarte‐Luís, Vanessa; Mota, Maria M.

doi:10.1038/nrmicro3504

Cited by 22 publications

(21 citation statements)

References 100 publications

(124 reference statements)

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“…Like Toxoplasma , many intracellular pathogens reside within a vacuole (pathogen‐containing vacuole or PV) in the host cytoplasm (Liehl et al , ). The PV membrane (PVM) protects these pathogens from detection by host cytosolic pathogen recognition receptor (PRR).…”

Section: Introductionmentioning

confidence: 99%

“…The PV membrane (PVM) protects these pathogens from detection by host cytosolic pathogen recognition receptor (PRR). However, the host has developed mechanisms to destroy the PV thereby exposing the pathogen (Liehl et al , ; Saeij & Frickel, ). For example, in mice interferons upregulate the expression of two families of large dynamin‐like GTPases: the immunity‐related GTPases (IRGs) and the guanylate‐binding proteins (GBPs) (Howard et al , ), which mediate the destruction of the PV of Toxoplasma and of many gram‐negative bacteria (Liehl et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

et al. 2020

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The protozoan parasite Toxoplasma gondii lives inside a vacuole in the host cytosol where it is protected from host cytoplasmic innate immune responses. However, IFNc-dependent cell-autonomous immunity can destroy the vacuole and the parasite inside. Toxoplasma strain differences in susceptibility to human IFNc exist, but the Toxoplasma effector(s) that determine these differences are unknown. We show that in human primary fibroblasts, the polymorphic Toxoplasma-secreted effector GRA15 mediates the recruitment of ubiquitin ligases, including TRAF2 and TRAF6, to the vacuole membrane, which enhances recruitment of ubiquitin receptors (p62/NDP52) and ubiquitin-like molecules (LC3B, GABARAP). This ultimately leads to lysosomal degradation of the vacuole. In murine fibroblasts, GRA15-mediated TRAF6 recruitment mediates the recruitment of immunity-related GTPases and destruction of the vacuole. Thus, we have identified how the Toxoplasma effector GRA15 affects cell-autonomous immunity in human and murine cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

et al. 2020

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“…Upon Toxoplasma infection, IFNγ mediates the deployment of a range of host defence molecules to the PV, ultimately leading to its disruption, autophagic elimination and inflammasome activation 9 . Central players in this defence mechanism are immunity-related GTPases (IRGs) 10–13 and guanylate binding proteins (GBPs) 14 .…”

Section: Introductionmentioning

confidence: 99%

TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles

Foltz

Napolitano

Khan

et al. 2017

Sci Rep

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Interferon gamma (IFNγ) is the major proinflammatory cytokine conferring resistance to the intracellular vacuolar pathogen Toxoplasma gondii by inducing the destruction of the parasitophorous vacuole (PV). We previously identified TRIM21 as an IFNγ-driven E3 ubiquitin ligase mediating the deposition of ubiquitin around pathogen inclusions. Here, we show that TRIM21 knockout mice were highly susceptible to Toxoplasma infection, exhibiting decreased levels of serum inflammatory cytokines and higher parasite burden in the peritoneum and brain. We demonstrate that IFNγ drives recruitment of TRIM21 to GBP1-positive Toxoplasma vacuoles, leading to Lys63-linked ubiquitination of the vacuole and restriction of parasite early replication without interfering with vacuolar disruption. As seen in vivo, TRIM21 impacted the secretion of inflammatory cytokines. This study identifies TRIM21 as a previously unknown modulator of Toxoplasma gondii resistance in vivo thereby extending host innate immune recognition of eukaryotic pathogens to include E3 ubiquitin ligases.

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“…Like Toxoplasma, many intracellular pathogens reside within a vacuole (pathogen-containing vacuole or PV) in the host cytoplasm (Liehl et al, 2015). The PV membrane (PVM) protects these pathogens from detection by host cytosolic pathogen recognition receptor (PRRs).…”

Section: Introductionmentioning

confidence: 99%

“…The PV membrane (PVM) protects these pathogens from detection by host cytosolic pathogen recognition receptor (PRRs). However, the host has developed mechanisms to destroy the PV thereby exposing the pathogen (Liehl et al, 2015;Saeij & Frickel, 2017). For example, in mice interferons upregulate the expression of two families of large dynamin-like GTPases: the immunity-related GTPases (IRGs) and the guanylate binding proteins (GBPs) (Howard et al, 2011), which mediate the destruction of the PV of Toxoplasma and of many gram-negative bacteria (Liehl et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

ToxoplasmaGRA15 limits parasite growth in IFNγ-activated fibroblasts through TRAF ubiquitin ligases

Mukhopadhyay

Sangaré

Braun

et al. 2020

Preprint

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The protozoan parasite Toxoplasma gondii lives inside a vacuole in the host cytoplasm where it is protected from host cytoplasmic innate immune responses. However, IFNγ-dependent cell-autonomous immunity can destroy the vacuole and the parasite inside. Toxoplasma strain differences in susceptibility to human IFNγ exist but the Toxoplasma effector(s) that determine these differences are unknown. We show that in human primary fibroblasts, the polymorphic Toxoplasma secreted effector GRA15 mediates the recruitment of ubiquitin ligases, including TRAF2 and TRAF6, to the vacuole membrane, which enhances recruitment of ubiquitin receptors (p62/NDP52) and ubiquitin-like molecules (LC3B, GABARAP). This ultimately leads to lysosomal degradation of the vacuole. In murine fibroblasts, GRA15-mediated TRAF6 recruitment mediates the recruitment of immunity-related GTPases and destruction of the vacuole. Thus, we have identified how the Toxoplasma effector GRA15 affects cell-autonomous immunity in human and murine cells.

show abstract

Unveiling the pathogen behind the vacuole

Cited by 22 publications

References 100 publications

Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles

ToxoplasmaGRA15 limits parasite growth in IFNγ-activated fibroblasts through TRAF ubiquitin ligases

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