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• W2114447275 abstract "Toxoplasma gondii is a world wide spread and obligate intracellular protozoan parasite, which induces mostly asymptomatic, lifelong persisting infections in humans. Furthermore, it is an important opportunistic pathogen of human beings also. T. gondii has evolved mechanisms to persist lifelong within its host, therefore a balanced parasite-host relationship plays an important role. In addition T. gondii changes different aspects in the host cell physiology and causes modulation of host cell compartments. The interaction with host cell signaling pathways, apoptosis and the inhibition of the poly(ADP-ribose) polymerase (PARP)-1 expression are affected likewise. PARP-1 is a nuclear protein and plays an important part in different cellular events including DNA repair, apoptosis, necrosis and regulation of gene expression. Further it is involved in the pathogenesis of different diseases like inflammational-chronical indispositions, ishemia and malaria. The goal of this work was to characterise the effect of an infection by T. gondii on PARP-1, to get further insights into the parasite-host interactions during a toxoplasmosis. PARP-1 protein levels were inhibited by T. gondii during the first minutes of infection of mouse macrophages in a dose-depending manner. This inhibition was also seen in different murin and human cell lines and therefore has to be a general phenomenon of T. gondii infections. Diminished PARP-1 protein levels were leading to a significant reduced ADP-ribosylation in infected host cells. Comparative experiments with virulent and avirulent T. gondii strains disproved the theory of a genotype- or virulence-depending PARP-1 inhibition. The inhibition occured posttranskriptional and independend of a functional translational machinery of the host cell. A Toxoplasma-induced PARP-1 degradation by the proteasome could be excluded through the use of proteasome inhibitors. Experiments with parasites pretreated differently showed a PARP-1 inhibition independent of the invasion and replication ability of T. gondii, because even dead parasites were able to inhibit PARP-1. The secretion of host cell molecules, which was induced by T. gondii infection, could be excluded as a basic mechanism. Whereas a direct contact between parasite and host cell was necessary, like experiments with a in vitro transwell system showed. A not further characterised effector molecule of the parasite membrane seems to be responsible for the downregulation of PARP-1, like a fractionation of parasite extracts suggested. The major surface antigen of T. gondii, SAG-1, could be excluded of beeing the parasitic effector molecule. Perhaps the effector molecule is a protease of T. gondii. To further characterise the functional importance of PARP-1 and its modulation by Toxoplasma, PARP-1 was stably overexpressed in mouse monocytes/macrophages (PARP-1high mutants). Interestingly, T. gondii was able to inhibit PARP-1 protein levels after infection in overexpressing mutants as well. The at least partly increased PARP-1 protein levels in PARPhigh mutants had no influence on invasion and replication of the parasite compared to wildtype cells. Expression profiles of NF-κB-regulated genes in PARP-1 overexpressing mutants and wildtype cells showed a parasite-mediated decrease of MIP-2, but not of TNF-α by PARP-1. Therefore the inhibition of PARP-1 by T. gondii could be a up to now unknown mechanism of the parasite to interact with pro-inflammatory chemokine-mediated defence mechanisms of the host cell. The at least partial overexpression of PARP-1 could not avoid the T. gondii-dependend inhibition of staurosporin-induced host cell apoptosis yet, but an effect on caspase-independend apoptosis pathways could not be excluded. This work gave new insights into correlations between T. gondii and the PARP-1 inhibition in host cells, which led to a better understanding of parasite-host interactions during toxoplasmosis." @default.
• W2114447275 created "2016-06-24" @default.
• W2114447275 creator A5053281651 @default.
• W2114447275 date "2022-02-17" @default.
• W2114447275 modified "2023-09-30" @default.
• W2114447275 title "Untersuchungen zur Inhibierung der Expression der Poly(ADP-ribose)Polymerase (PARP) nach Infektion mit Toxoplasma gondii" @default.
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