Murine Guanylate Binding Protein 2 (mGBP2) controls<i>Toxoplasma gondii</i>replication

Degrandi, Daniel; Kravets, Elisabeth; Konermann, Carolin; Beuter-Gunia, Cornelia; Klümpers, Verena; Lahme, Sarah; Wischmann, Eva; Mausberg, Anne K.; Beer‐Hammer, Sandra; Pfeffer, Klaus

doi:10.1073/pnas.1205635110

Cited by 174 publications

(247 citation statements)

References 38 publications

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“…S3). Previous reports have demonstrated that mouse GBPs are involved in T. gondii growth inhibition (18,25,26). Accordingly, we analyzed the expression of GBP family members in human MSCs before and after IFN-γ treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Mice defective in p65 GTPases were highly susceptible to T. gondii infection, and GBPs deleted in chromosome 3 aneuploid macrophages were defective in IFN-γ-mediated inhibition of intracellular parasite growth (18). The recruitment of mGBP2 to T. gondii-containing PVs is essential for a cell's ability to control T. gondii replication (25). Furthermore, recruitment of mGBP1 to PVs is associated with vesiculation and rupture and thus also protects against T. gondii infection (26).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recruitment of mGBP1 to PVs is associated with vesiculation and rupture and thus also protects against T. gondii infection (26). Both mGBP1 and mGBP2 have been shown to form tetramers and may also heterooligomerize to cooperatively activate GTPase activity (25).…”

Section: Discussionmentioning

confidence: 99%

“…Recruitment of mouse GBPs to the PV was reported to be essential for the replication control of T. gondii (18,25,26). To explore the role of hGBP1 in human MSCs, we used immunofluorescence to assess its intracellular localization after T. gondii infection.…”

Section: Human Gbp1 Is Recruited To the Parasitophorous Vacuole Durinmentioning

confidence: 99%

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Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Qin

Lai

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stromal cells (MSCs) have recently been shown to play important roles in mammalian host defenses against intracellular pathogens, but the molecular mechanism still needs to be clarified. We confirmed that human MSCs (hMSCs) prestimulated with IFN-γ showed a significant and dose-dependent ability to inhibit the growth of two types of Toxoplasma gondii [type I RH strain with green fluorescent proteins (RH/GFP) or type II PLK strain with red fluorescent proteins (PLK/RED)]. However, in contrast to previous reports, the anti-T. gondii activity of hMSCs was not mediated by indoleamine 2,3-dioxygenase (IDO). Genome-wide RNA sequencing (RNA-seq) analysis revealed that IFN-γ increased the expression of the p65 family of human guanylate-binding proteins (hGBPs) in hMSCs, especially hGBP1. To analyze the functional role of hGBPs, stable knockdowns of hGBP1, -2, and -5 in hMSCs were established using a lentiviral transfection system. hGBP1 knockdown in hMSCs resulted in a significant loss of the anti-T. gondii host defense property, compared with hMSCs infected with nontargeted control sequences. hGBP2 and -5 knockdowns had no effect. Moreover, the hGBP1 accumulation on the parasitophorous vacuole (PV) membranes of IFN-γ-stimulated hMSCs might protect against T. gondii infection. Taken together, our results suggest that hGBP1 plays a pivotal role in anti-T. gondii protection of hMSCs and may shed new light on clarifying the mechanism of host defense properties of hMSCs.human stem cells | parasitic protozoan | innate immunity | in vitro cultivation

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Human Gbp1 Is Recruited To the Parasitophorous Vacuole Durinmentioning

confidence: 99%

See 2 more Smart Citations

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Qin

Lai

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…IFN-g activates antiparasite programs involving IFN-g-inducible GTPases such as p47 IFN-g-regulated GTPases (IRGs) and p65 guanylate-binding protein (GBPs) (8). Mice deficient in IRGs such as LRG-47 (also known as Irgm1), IGTP (Irgm3) or IIGP1 (Irga6), or GBPs displayed loss of resistance to T. gondii infection (9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Ohshima

Lee

Sasai

et al. 2014

The Journal of Immunology

112

127

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IFN-γ mediates cellular innate immunity against an intracellular parasite, Toxoplasma gondii, by inducing immunity-related GTPases such as p47 IFN-γ–regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti–T. gondii cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti–T. gondii cellular immunity by recruiting IFN-γ–inducible GTPases. IFN-γ–induced suppression of T. gondii proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti–T. gondii response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti–T. gondii cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ–mediated anti–T. gondii responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ–induced inhibition of T. gondii proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ–induced recruitment of the immunity-related GTPases to the intracellular pathogen.

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Host Factors that Recruit Autophagy as Defense AgainstToxoplasma Gondii

Subauste

2014

Autophagy, Infection, and the Immune Response

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Murine Guanylate Binding Protein 2 (mGBP2) controlsToxoplasma gondiireplication

Cited by 174 publications

References 38 publications

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Host Factors that Recruit Autophagy as Defense AgainstToxoplasma Gondii

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