<i>Trypanosoma cruzi</i>
            Targets Akt in Host Cells as an Intracellular Antiapoptotic Strategy

Chuenkova, Marina V.; PereiraPerrin, Mercio

doi:10.1126/scisignal.2000374

Cited by 56 publications

(55 citation statements)

References 62 publications

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“…The infected cell, however, has the capacity to initiate its own death by apoptosis. This potent defense mechanism exerts strong selective pressure on T. cruzi, which has evolved strategies to modulate the target cell apoptotic program in its favor [8][9][10][11]. Related to this, the first study showing that T. cruzi infection promotes the prolonged survival of cardiomyocytes was reported by our group [12].…”

Section: Introductionmentioning

confidence: 81%

Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Ponce

Cano

Silva

et al. 2011

Med Microbiol Immunol

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Local innate immunity plays a key role in initiating and coordinating homeostatic and defense responses in the heart. We have previously reported that the cardiotropic parasite Trypanosoma cruzi, the etiological agent of Chagas disease, protects cardiomyocytes against growth factor deprivation-induced apoptosis. In this study, we investigated cardiomyocyte innate immune response to T. cruzi infection and its role in cellular protection from apoptosis. We found that Toll-like receptor (TLR) 2-expressing cells were strongly increased by the parasite in BALB/c neonatal mouse cardiomyocyte cultures. Using a dominant-negative system, we showed that TLR2 mediated cardiomyocyte survival and the secretion of interleukin (IL) 6, which acted as an essential anti-apoptotic factor. Moreover, IL6 released by infected cells, as well as the recombinant bioactive cytokine, induced the phosphorylation of the signal transducers and activators of transcription-3 (STAT3) in cultured cardiomyocytes. In accord with the in vitro results, during the acute phase of the infection, TLR2 expression increased 2.9-fold and the anti-apoptotic factor Bcl-2 increased 4.5-fold in the cardiac tissue. We have clearly shown a cross-talk between the intrinsic innate response of cardiomyocytes and the pro-survival effect evoked by the parasite.

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Section: Introductionmentioning

confidence: 81%

Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Ponce

Cano

Silva

et al. 2011

Med Microbiol Immunol

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“…This binding is mediated by the parasite-derived neurotrophic factor (PDNF), a trans-sialidase located on the surface of the parasite. PDNF in the cytosol of the host cell apparently activates Akt signaling, leading to a suppression of apoptosis (10). Furthermore, T. cruzi trans-sialidase binds to endothelial cells, triggering activation of NF-B and leading to protection against apoptosis caused by growth factor deprivation (13).…”

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confidence: 99%

Trypanosoma cruzi Infection Induces a Global Host Cell Response in Cardiomyocytes

et al. 2011

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Chagas' disease, caused by the hemoflagellate protozoan Trypanosoma cruzi, affects millions of people in South and Central America. Chronic chagasic cardiomyopathy, the most devastating manifestation of this disease, occurs in approximately one-third of infected individuals. Events associated with the parasite's tropism for and invasion of cardiomyocytes have been the focus of intense investigation in recent years. In the present study, we use murine microarrays to investigate the cellular response caused by invasion of primary murine cardiomyocytes by T. cruzi trypomastigotes. These studies identified 353 murine genes that were differentially expressed during the early stages of invasion and infection of these cells. Genes associated with the immune response, inflammation, cytoskeleton organization, cell-cell and cell-matrix interactions, apoptosis, cell cycle, and oxidative stress are among those affected during the infection. Our data indicate that T. cruzi induces broad modulations of the host cell machinery in ways that provide insight into how the parasite survives, replicates, and persists in the infected host and ultimately defines the clinical outcome of the infection.

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“…5 Exploiting AKT pathway to inhibit host cell apoptosis has also been documented during infection with Salmonella, Anaplasma, Toxoplasma and Trypanosome. 6,7 Host immune activation essential to eliminate intracellular pathogens is also negatively modulated by AKT 8 and constitutively active AKT was shown to increase the LPSinduced production of anti-inflammatory cytokine IL-10 (ref 9) and to down-regulate p65 and GSK-3β (ref 10). Two major proteins which contribute in diversifying AKT signaling are β-catenin and FOXO-1.…”

mentioning

confidence: 99%

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

et al. 2016

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In order to establish infection, intra-macrophage parasite Leishmania donovani needs to inhibit host defense parameters like inflammatory cytokine production and apoptosis. In the present study, we demonstrate that the parasite achieves both by exploiting a single host regulator AKT for modulating its downstream transcription factors, β-catenin and FOXO-1. L. donovaniinfected RAW264.7 and bone marrow-derived macrophages (BMDM) treated with AKT inhibitor or dominant negative AKT constructs showed decreased anti-inflammatory cytokine production and increased host cell apoptosis resulting in reduced parasite survival. Infection-induced activated AKT triggered phosphorylation-mediated deactivation of its downstream target, GSK-3β. Inactivated GSK-3β, in turn, could no longer sequester cytosolic β-catenin, an anti-apoptotic transcriptional regulator, as evidenced from its nuclear translocation during infection. Constitutively active GSK-3β-transfected L. donovani-infected cells mimicked the effects of AKT inhibition and siRNA-mediated silencing of β-catenin led to disruption of mitochondrial potential along with increased caspase-3 activity and IL-12 production leading to decreased parasite survival. In addition to activating antiapoptotic β-catenin, phospho-AKT inhibits activation of FOXO-1, a pro-apoptotic transcriptional regulator. Nuclear retention of FOXO-1, inhibited during infection, was reversed when infected cells were transfected with dominant negative AKT constructs. Overexpression of FOXO-1 in infected macrophages not only documented increased apoptosis but promoted enhanced TLR4 expression and NF-κB activity along with an increase in IL-1β and decrease in IL-10 secretion. In vivo administration of AKT inhibitor significantly decreased liver and spleen parasite burden and switched cytokine balance in favor of host. In contrast, GSK-3β inhibitor did not result in any significant change in infectivity parameters. Collectively our findings revealed that L. donovani triggered AKT activation to regulate GSK-3β/β-catenin/FOXO-1 axis, thus ensuring inhibition of both host cell apoptosis and immune response essential for its intra-macrophage survival.

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Trypanosoma cruzi Targets Akt in Host Cells as an Intracellular Antiapoptotic Strategy

Cited by 56 publications

References 62 publications

Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Trypanosoma cruzi Infection Induces a Global Host Cell Response in Cardiomyocytes

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

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