Interferon-γ Restricts Toxoplasma gondii Development in Murine Skeletal Muscle Cells via Nitric Oxide Production and Immunity-Related GTPases

Takács, Anna C.; Swierzy, Izabela; Lüder, Carsten G. K.

doi:10.1371/journal.pone.0045440

Cited by 38 publications

(32 citation statements)

References 62 publications

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“…S7. In mice, astrocytes can use IRGs to restrict T. gondii infection; mMSCs use iNOS to produce NO; and skeletal muscle cells use both mechanisms (27). The mGBPs may also critically contribute to fighting T. gondii replication in vivo (18).…”

Section: Discussionmentioning

confidence: 99%

“…The iNOS-mediated production of NO is a well-known molecular effector against pathogens in the innate immune responses of various animals, including mMSCs (9) and skeletal muscle cells (27), and also in vivo (15,30,31). However, a previous study reported that iNOS protein expression was not detectable in human MSCs (9).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that an IRG protein-based resistance mechanism is essential to control T. gondii replication in mice (17,27). Numerous IRGs were found to converge on vacuoles containing T. gondii in IFN-γ-activated mouse macrophages, fibroblasts, and astrocytes (32)(33)(34).…”

Section: Discussionmentioning

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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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Parasites that escape this response then disseminate throughout the host and IFNγ production by innate and adaptive cells is required for control of parasite growth (19). The mechanisms by which IFNγ operate to limit tachyzoite proliferation include induction of immunity-related GTPases and inducible nitric oxide synthase in a number of host cell types including M1 (20, 21). Immune pressure induces the transition of parasite to slow growing tissue cysts (bradyzoites) that resides in the skeletal muscle and central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

Jin

Blair

Warunek

et al. 2017

The Journal of Immunology

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The coordination of macrophage polarization is essential for the robust regenerative potential of skeletal muscle. Repair begins with an inflammatory monocyte/pro-inflammatory macrophage (M1)-mediated phase followed by polarization to a pro-regenerative (M2) phenotype. Recently, regulatory T cells (Tregs) were described as necessary for this M1 to M2 transition. Here, we report that chronic infection with the protozoan parasite Toxoplasma gondii causes a non-resolving Th1 myositis with prolonged tissue damage associated with persistent M1 accumulation. Surprisingly, Treg ablation during chronic infection rescues macrophage homeostasis and skeletal muscle fiber regeneration showing that Tregs can directly contribute to muscle damage. This study provides evidence that the tissue environment established by the parasite could lead to a paradoxical pathogenic role for Tregs. As such, these findings should be considered when tailoring therapies directed at Tregs in inflammatory settings.

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“…It is widely accepted that the status of the hosts' immune function is a critical determinant for the outcome of T. gondii infection [17, 18]. Stress is one important factor affecting the immune function of animals.…”

Section: Introductionmentioning

confidence: 99%

Activation of chronic toxoplasmosis by transportation stress in a mouse model

et al. 2016

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Toxoplasma gondiiis an obligate intracellular parasite infecting 25% of the world population and enormous number of animals. It can exist in two forms in intermediate hosts: the fast replicating tachyzoites responsible for acute infection and the slowly replicating bradyzoites responsible for life-long chronic infection. The interconversion between tachyzoites and bradyzoites plays critical roles in the transmission and pathogenesis of T. gondii. However, the molecular mechanisms that govern the interconversion are largely unknown. In this study, we established a chronic infection model in mice and examined the impact of transportation stress on the status of chronic infection. Our results demonstrated that, treating chronically infected mice with conditions mimicking transportation stress reduced the levels of several key cytokines that restrict the infection at chronic stage. Increased expression of the tachyzoite specific gene SAG1 (surface antigen 1) was detected in brain cysts of stress treated mice, indicating activation and conversion of bradyzoites to tachyzoites. Using this model, we identified fifteen toxoplasmic proteins that had significant abundance changes during stress induced cysts reactivation. These proteins serve as a basis for further investigation of the mechanisms governing bradyzoite conversion.

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Interferon-γ Restricts Toxoplasma gondii Development in Murine Skeletal Muscle Cells via Nitric Oxide Production and Immunity-Related GTPases

Cited by 38 publications

References 62 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

Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection

Activation of chronic toxoplasmosis by transportation stress in a mouse model

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