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      Exogenous tumor necrosis factor-alpha could induce egress of Toxoplasma gondii from human foreskin fibroblast cells Translated title: Le facteur alpha de nécrose tumorale exogène pourrait induire la sortie de Toxoplasma gondii des fibroblastes de prépuce humain

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      EDP Sciences

      Toxoplasma gondii, TNF-α, egress, apoptosis,

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          Toxoplasma gondii is an intra-cellular protozoan parasite that can infect almost all nucleated cells, eliciting host immune responses against infection. Host tissue damage is mainly caused by cellular lysis when T. gondii egresses from infected cells. However, the effects of cytokines released by host immune cells on egression of T. gondii remain elusive. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) on the egress of T. gondii from infected human foreskin fibroblast (HFF) cells and to elucidate the underlying mechanisms that regulate TNF-α-induced egress. Using flow cytometry to count tachyzoites of T. gondii released into cell culture medium, we found that egress of T. gondii from infected HFF cells could be induced by 10 ng/mL TNF-α in a time-dependent manner. Pre-treatment of infected HFF cells with BAPTA-AM to chelate intra-parasitic calcium could greatly inhibit TNF-α-induced egress. Similar results were obtained when using cytochalasin D to block parasite motility before the TNF-α-induced egress assay. In addition, blocking host apoptosis by Z-VAD-FMK could decrease TNF-α induced egress, while blocking necroptosis by necrostatin-1 has little impact on TNF-α-induced egress. The egressed tachyzoites displayed a normal growth rate and lost no virulence. Our results suggest that host cytokines could influence the cellular lytic processes of T. gondii, providing new insights into the relationship between host TNF-α and T. gondii pathogenesis.

          Translated abstract

          Toxoplasma gondii est un parasite protozoaire intracellulaire qui peut infecter presque toutes les cellules nucléées, provoquant des réponses immunitaires de l'hôte contre l'infection. Les lésions tissulaires de l'hôte sont principalement causées par la lyse cellulaire lorsque T. gondii sort des cellules infectées. Cependant, les effets des cytokines libérées par les cellules immunitaires de l'hôte sur la sortie de T. gondii étaient peu connus. Cette étude vise à étudier le rôle du facteur de nécrose tumorale alpha (TNF-α) sur la sortie de T. gondii de cellules infectées de fibroblastes de prépuce humain (FPH) et à élucider les mécanismes sous-jacents qui régulent la sortie induite par le TNF-α. En utilisant la cytométrie de flux pour compter les tachyzoïtes de T. gondii libérés dans le milieu de culture cellulaire, nous avons trouvé que la sortie de T. gondii des cellules FPH infectées pouvait être induite par 10 ng/ml de TNF-α, de manière dépendante du temps. Le prétraitement des cellules FPH infectées par BAPTA-AM pour chélater le calcium intra-parasitaire inhibe beaucoup la sortie induite par le TNF-α. Des résultats similaires ont été obtenus en utilisant la cytochalasine D pour bloquer la motilité du parasite avant le test de sortie induite par le TNF-α. De plus, le blocage de l'apoptose de l'hôte par Z-VAD-FMK diminue la sortie induite par le TNF-α, tandis que le blocage de la nécroptose par la nécrostatine-1 a peu d'impact sur la sortie induite par le TNF-α. Les tachyzoïtes évacués avaient un taux de croissance normal et n'ont perdu aucune virulence. Nos résultats suggèrent que les cytokines de l'hôte pourraient influencer le processus lytique cellulaire de T. gondii et fournissent de nouvelles informations sur la relation entre TNF-α de l'hôte et pathogenèse de T. gondii.

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          Most cited references 22

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          Toxoplasmic encephalitis in AIDS.

           B Luft,  S J Remington (1992)
          Involvement of the central nervous system (CNS) is common in patients with advanced disease due to human immunodeficiency virus (HIV). Symptoms range from lethargy and apathy to coma, incoordination and ataxia to hemiparesis, loss of memory to severe dementia, and focal to major motor seizures. Involvement may be closely associated with HIV infection per se, as in the AIDS dementia complex, but is frequently caused by opportunistic pathogens such as Toxoplasma gondii and Cryptococcus neoformans or malignancies such as primary lymphoma of the CNS. The clinical presentations of attendant and direct CNS involvement are remarkably non-specific and overlapping, yet a correct diagnosis is critical to successful intervention. Toxoplasmic encephalitis is one of the most common and most treatable causes of AIDS-associated pathology of the CNS. A great deal has been learned in the last 10 years about its unique presentation in the HIV-infected patient with advanced disease. Drs. Benjamin J. Luft of the State University of New York at Stony Brook and Jack S. Remington of the Stanford University School of Medicine and Palo Alto Medical Foundation's Research Institute have studied T. gondii for many years and are two of the leading experts in the field. This commentary comprises an update of their initial review (J Infect Dis 1988;157:1-6) and a presentation of the current approaches to diagnosing and managing toxoplasmic encephalitis in HIV-infected patients.
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            In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha.

            To examine the function of IL-10 synthesis during early infection with the intracellular protozoan Toxoplasma gondii, IL-10 knockout (KO) mice were inoculated with an avirulent parasite strain (ME-49). In contrast to control littermates that displayed 100% survival, the IL-10-deficient animals succumbed within the first 2 wk of the infection, with no evidence of enhanced parasite proliferation. The mortality in the IL-10 KO mice was associated with enhanced liver pathology characterized by increased cellular infiltration and intense necrosis. Levels of IL-12 and IFN-gamma in sera of infected IL-10-deficient animals were four- to sixfold higher than those in sera from control mice, as were mRNA levels for IFN-gamma, IL-1 beta, TNF-alpha, and IL-12 in lung tissue. Similarly, macrophages from IL-10 KO mice activated in vitro or in vivo with T. gondii produced higher levels of TNF-alpha and IL-12 than macrophages from control animals. Moreover, spleen cells from IL-10 KO mice infected with T. gondii secreted more IFN-gamma than splenocytes from nondeficient animals. In vitro depletion experiments indicated that CD4+ lymphocytes are the major source of the latter cytokine in the spleen cell populations, and in vivo depletion with anti-CD4 Abs protected the IL-10 KO mice from parasite-induced mortality. Together the data suggest that endogenous IL-10 synthesis plays an important role in vivo in down-regulating monokine and IFN-gamma responses to acute intracellular infection, thereby preventing host immunopathology.
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              Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma

              Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge1. This process regulates diverse cellular functions like plasma membrane repair in plants and animals2,3, discharge of defensive spikes in Paramecium 4, and secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chemical transmitters from neurons5. In animal cells, serine/threonine kinases including PKA, PKC and CaM-kinases have been implicated in calcium-signal transduction leading to regulated secretion1,6,7. Although plants and protozoa also regulate secretion via intracellular calcium, the means by which these signals are relayed have not been elucidated. Here we demonstrate that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. This phenotype was recapitulated using a chemical biology approach, wherein pyrazolopyrimidine-derived compounds specifically inhibited TgCDPK1 and disrupted the parasite life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, since expression of a resistant kinase mutant reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates8, suggesting that related CDPKs may play a role in calcium-regulated secretion in other organisms. Since this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemotherapy against T. gondii and related apicomplexans.

                Author and article information

                EDP Sciences
                27 November 2017
                : 24
                : ( publisher-idID: parasite/2017/01 )
                [1 ] Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Microbiology and Parasitology; Laboratory of Tropical and Parasitic Diseases Control; Anhui Medical University, Hefei, Anhui 230032 China
                Author notes
                [* ]Corresponding author: jiyongshengkey@ 123456hotmail.com
                parasite170070 10.1051/parasite/2017051
                © Y. Yao et al., published by EDP Sciences, 2017

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 23, Pages: 7
                Research Article

                apoptosis, toxoplasma gondii, tnf-α, egress


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