Inflammatory early events associated to the role of P2X7 receptor in acute murine toxoplasmosis

Corrêa, Gladys; Lindenberg, Carolina de A.; Moreira-Souza, Aline Cristina Abreu; Savio, Luiz Eduardo Baggio; Takiya, Christina Maeda; Marques-da-Silva, Camila; Vommaro, Rossiane C.; Coutinho‐Silva, Robson

doi:10.1016/j.imbio.2016.12.007

Cited by 32 publications

(25 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The high susceptibility of P2X7R KO mice to T. gondii compared to their WT counterpart were also confirmed in a model of acute toxoplasmosis. P2X7R KO mice succumbed faster to the infection, lost more weight, had higher parasitic loads and produced less pro-inflammatory cytokines than WT mice after intra peritoneal infections with two different strains RH or ME49 (Miller et al, 2011 ; Corrêa et al, 2016 ).…”

Section: Eatp and P2x7 Receptor: The Killer Side Of The Forcementioning

confidence: 99%

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

Petit-Jentreau

Tailleux

Coombes

2017

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Immune responses are essential for the protection of the host against external dangers or infections and are normally efficient in the clearance of invading microbes. However, some intracellular pathogens have developed strategies to replicate and survive within host cells resulting in latent infection associated with strong inflammation. This excessive response can cause cell and tissue damage and lead to the release of the intracellular content, in particular the nucleotide pool, into the extracellular space. Over the last decade, new studies have implicated metabolites from the purinergic pathway in shaping the host immune response against intracellular pathogens and proved their importance in the outcome of the infection. This review aims to summarize how the immune system employs the purinergic system either to fight the pathogen, or to control collateral tissue damage. This will be achieved by focusing on the macrophage response against two intracellular pathogens, the human etiologic agent of tuberculosis, Mycobacterium tuberculosis and the protozoan parasite, Toxoplasma gondii.

show abstract

Section: Eatp and P2x7 Receptor: The Killer Side Of The Forcementioning

confidence: 99%

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

Petit-Jentreau

Tailleux

Coombes

2017

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…As toxoplasmosis is an inflammatory disease, the killing of T. gondii requires both innate and adaptive immune responses ( 40 ). Several lines of evidence—from gene polymorphism data to mouse knockout analysis—support the notion that P2X7 receptor activity contributes to control toxoplasmosis infection in vivo , by triggering antimicrobial activities in the intracellular environment (such as ROS production and lysosome fusion to the parasitophorous vacuole), and by stimulating pro-inflammatory events, such as the production of IL-12, IL-1β, and IFN-γ ( 27 , 32 ). However, the downstream pathways that lead to parasite elimination via P2X7 receptor activation had not been dissected previously.…”

Section: Discussionmentioning

confidence: 98%

“…Our group demonstrated that P2X7 receptor activation by extracellular ATP (eATP) in T. gondii -infected macrophages contributes to parasite elimination by ROS production and lysosome fusion with the parasitophorous vacuole ( 26 ). We also showed that the P2X7 receptor is an important activator of the anti-parasitic pro-inflammatory response that occurs in early T. gondii infection in vivo ( 32 ). However, the cascade of intracellular events trigged by purinergic signaling—which results in parasite control in early infection—remains to be elucidated.…”

Section: Introductionmentioning

confidence: 88%

“…Polymorphisms in the human P2X7 receptor are directly associated with host susceptibility to congenital or acquired toxoplasmosis, in immunocompetent patients ( 25 , 31 ). Also, P2X7 absence or disruption of P2X7 receptor function increases toxoplasmosis severity in murine infection with virulent (RH, type I) or non-virulent (Me-49, type II) strains of T. gondii ( 27 , 32 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The P2X7 Receptor Mediates Toxoplasma gondii Control in Macrophages through Canonical NLRP3 Inflammasome Activation and Reactive Oxygen Species Production

et al. 2017

Self Cite

View full text Add to dashboard Cite

Toxoplasma gondii (T. gondii) is the protozoan parasite that causes toxoplasmosis, a potentially fatal disease to immunocompromised patients, and which affects approximately 30% of the world’s population. Previously, we showed that purinergic signaling via the P2X7 receptor contributes to T. gondii elimination in macrophages, through reactive oxygen species (ROS) production and lysosome fusion with the parasitophorous vacuole. Moreover, we demonstrated that P2X7 receptor activation promotes the production of anti-parasitic pro-inflammatory cytokines during early T. gondii infection in vivo. However, the cascade of signaling events that leads to parasite elimination via P2X7 receptor activation remained to be elucidated. Here, we investigated the cellular pathways involved in T. gondii elimination triggered by P2X7 receptor signaling, during early infection in macrophages. We focused on the potential role of the inflammasome, a protein complex that can be co-activated by the P2X7 receptor, and which is involved in the host immune defense against T. gondii infection. Using peritoneal and bone marrow-derived macrophages from knockout mice deficient for inflammasome components (NLRP3−/−, Caspase-1/11−/−, Caspase-11−/−), we show that the control of T. gondii infection via P2X7 receptor activation by extracellular ATP (eATP) depends on the canonical inflammasome effector caspase-1, but not on caspase-11 (a non-canonical inflammasome effector). Parasite elimination via P2X7 receptor and inflammasome activation was also dependent on ROS generation and pannexin-1 channel. Treatment with eATP increased IL-1β secretion from infected macrophages, and this effect was dependent on the canonical NLRP3 inflammasome. Finally, treatment with recombinant IL-1β promoted parasite elimination via mitochondrial ROS generation (as assessed using Mito-TEMPO). Together, our results support a model where P2X7 receptor activation by eATP inhibits T. gondii growth in macrophages by triggering NADPH-oxidase-dependent ROS production, and also by activating a canonical NLRP3 inflammasome, which increases IL-1β production (via caspase-1 activity), leading to mitochondrial ROS generation.

show abstract

“…Toxoplasma gondii appears to activate both NLRP1 and NLRP3 [24], yet the specificity of this activation remains elusive. While the activation of NLRP3 in response to T. gondii appears to be influenced by P2X7 receptor-dependent potassium efflux and the induction of reactive oxygen species [47,[49][50][51], the exact mechanisms of how T. gondii activates multiple inflammasomes remain enigmatic. In this context it is also interesting to note that in vitro infection of mouse macrophages and human monocytes with T. gondii only leads to the secretion of IL-1β, but not IL-18 [24,52].…”

Section: Interventionsmentioning

confidence: 99%

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Kupz

Pai

Giacomin

et al. 2019

Preprint

View full text Add to dashboard Cite

24Toxoplasmic encephalitis is an AIDS-defining condition in HIV + individuals. The decline of 25 IFN-γ-producing CD4 + T cells in AIDS is a major contributing factor in reactivation of 26 quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important 27 to identify CD4-independent mechanisms to control acute T. gondii infection. Here we have 28 investigated the targeted expansion and regulation of IFN-γ production by CD8 + T cells, DN T 29 cells and NK cells in response to T. gondii infection using IL-2 complex (IL2C) pre-treatment 30 in an acute in vivo mouse model. Our results show that expansion of CD8 + T cells, DN T cells 31 and NK cell by S4B6 IL2C treatment increases survival rates of mice infected with T. gondii 32 and this increased survival is dependent on both IL-12-and IL-18-driven IFN-γ production. 33 Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of 34 active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic 35 cell types but independent from T. gondii-derived dense granule (GRA) proteins. Our results 36 provide evidence for a protective role of IL2C-mediated expansion of CD8 + T cells, DN T cells 37 and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute 38 toxoplasmosis. 39 40 41 3 Author Summary 42A third of the world's population is chronically infected with the parasite Toxoplasma gondii. 43 In most cases the infection is asymptomatic, but in individuals suffering from AIDS, 44 reactivation of brain and muscle cysts containing T. gondii is a significant cause of death. The 45 gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing 46 factor in reactivation of T. gondii infection and the development of acute disease. In this study, 47 we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease 48 and premature death via increased availability of interferon gamma-producing immune cells. 49 We also demonstrate that the upstream signaling molecule interleukin-18 is required for the 50 protective immune response by non-CD4 cells and show that the sensing of active parasite 51 invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell 52 expansion may be a promising therapy in toxoplasmosis and suggests that the development of 53 novel intervention strategies targeting danger recognition pathways may be useful against 54 toxoplasmosis, particularly in the context of AIDS. 55 57 [1]. It is estimated that one-third of the world's population is infected with T. gondii. In most 58 individuals, infection is asymptomatic and leads to chronic, life-long persistence of T. gondii-59 containing cysts, primarily in brain and muscle tissue [2]. Active disease, also known as 60 toxoplasmosis, usually occurs after reactivation of encysted parasites, and is often associated 61 with immunosuppression. If untreated, toxoplasmosis may be fatal. Addi...

show abstract

Inflammatory early events associated to the role of P2X7 receptor in acute murine toxoplasmosis

Cited by 32 publications

References 37 publications

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

The P2X7 Receptor Mediates Toxoplasma gondii Control in Macrophages through Canonical NLRP3 Inflammasome Activation and Reactive Oxygen Species Production

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Contact Info

Product

Resources

About