Neuronal gp130 Expression Is Crucial to Prevent Neuronal Loss, Hyperinflammation, and Lethal Course of Murine Toxoplasma Encephalitis

Händel, Ulrike; Brunn, Anna; Drögemüller, Katrin; Müller, Werner; Deckert, Martina; Schlüter, Dirk

doi:10.1016/j.ajpath.2012.03.029

Cited by 40 publications

(24 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T. gondii -infected cells are surprisingly resistant against induction of PCD in vitro and in vivo 28293031323335363742. Here, we identify the Apaf-1 apoptosome as a hitherto unrecognized target of T. gondii to inhibit caspase-dependent intrinsic host cell death.…”

Section: Discussionmentioning

confidence: 91%

“…It is believed that anti-apoptotic activities of T. gondii also counteract the innate PCD program with which infected host cells would normally respond to infection 10283334. Importantly, during Toxoplasma encephalitis in mice, parasite-infected host cells are also protected from undergoing inflammation-associated PCD 3536. Release of cytochrome c from mitochondria to the host cell cytosol is profoundly decreased in parasite-positive cells 3032 and this is at least in part due to reduced activation of the pro-apoptotic Bcl-2 effector protein Bax 37.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Graumann

Schaumburg

Reubold

et al. 2015

MIC

View full text Add to dashboard Cite

Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell-free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome c in vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo-apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Graumann

Schaumburg

Reubold

et al. 2015

MIC

View full text Add to dashboard Cite

show abstract

“…We hypothesized in the present study that neuron apoptosis noted in TE might not be, at least in part, a result from the primary injury by parasitism but from the secondary response to microglia activation, which gives rise to the subsequent neuron cell damage, and is closely associated with the TE symptoms and signs [31]. …”

Section: Discussionmentioning

confidence: 99%

Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis

Zhang

Chen

et al. 2014

Parasites Vectors

View full text Add to dashboard Cite

BackgroundA plethora of evidence shows that activated microglia play a critical role in the pathogenesis of the central nervous system (CNS). Toxoplasmic encephalitis (TE) frequently occurs in HIV/AIDS patients. However, knowledge remains limited on the contributions of activated microglia to the pathogenesis of TE.MethodsA murine model of reactivated encephalitis was generated in a latent infection with Toxoplasma gondii induced by cyclophosphamide. The neuronal apoptosis in the CNS and the profile of pro-inflammatory cytokines were assayed in both in vitro and in vivo experiments.ResultsMicroglial cells were found to be activated in the cortex and hippocampus in the brain tissues of mice. The in vivo expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) were up-regulated in TE mice, and accordingly, the neuronal apoptosis was significantly increased. The results were positively correlated with those of the in vitro experiments. Additionally,apoptosis of the mouse neuroblastoma type Neuro2a (N2a) remarkably increased when the N2a was co-cultured in transwell with microglial cells and Toxoplasma tachyzoites. Both in vivo and in vitro experiments showed that minocycline (a microglia inhibitor) treatment notably reduced microglial activation and neuronal apoptosis.ConclusionsActivated microglia contribute to neuronal apoptosis in TE and inhibition of microglia activation might represent a novel therapeutic strategy of TE.

show abstract

“…The multiple interactions of this pleiotropic cytokine merit further investigation. IL-6 has been demonstrated to be necessary for anti-T. gondii immunity (26), but an imbalance of IL-6 signaling through the gp130 receptor subunit could make IL-6 a pathological rather than protective factor (27). The key factor deciding between these extremes, also during T. gondii infection, is probably SOCS3 (28).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6-Driven Inflammatory Response Induces Retinal Pathology in a Model of Ocular Toxoplasmosis Reactivation

et al. 2015

View full text Add to dashboard Cite

c Ocular inflammation is one of the consequences of infection with the protozoan parasite Toxoplasma gondii. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-␥), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-Toxoplasma antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-␥ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis. O cular toxoplasmosis (OT), a sequel of infection with the apicomplexan parasite Toxoplasma gondii, is a major cause of visual impairment worldwide, responsible for 30 to 50% of posterior uveitis in immunocompetent people. While OT was considered until recently as being exclusively due to congenital infection, screening of Toxoplasma-seropositive persons in Europe and North America revealed that 1 to 2% of this population presents retinal toxoplasmic lesions (1). Thus, possible reactivation of these ocular infections in postnatally infected individuals poses a hitherto underestimated problem for the health systems in these countries (2) and even more so in regions like South America (3, 4). At the moment, no treatment has so far achieved a consistently reduced risk of reactivation, except perhaps in high-risk patients (5, 6). To establish more specific, immune-based interventions, we need to elucidate the physiopathology of OT, which is so far largely ignored. Therefore, we wanted to gather novel data on the immune responses involved in retinal T. gondii reactivation. The long-term objective of this model is to open new therapeutic perspectives of human OT.The main obstacle for thorough research of ocular reactivation is the absence of a suitable mouse model (4). After oral or intraper...

show abstract

Neuronal gp130 Expression Is Crucial to Prevent Neuronal Loss, Hyperinflammation, and Lethal Course of Murine Toxoplasma Encephalitis

Cited by 40 publications

References 34 publications

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis

Interleukin-6-Driven Inflammatory Response Induces Retinal Pathology in a Model of Ocular Toxoplasmosis Reactivation

Contact Info

Product

Resources

About