Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.
Gabrielle GayLaurence BraunMarie-Pierre Brenier-PinchartJulien VollaireVéronique JosserandRose-Laurence BertiniAurélie VaresanoBastien TouquetPieter-Jan De BockYohann CoutIsabelle TardieuxAlexandre BougdourMohamed-Ali HakimiPublished in: The Journal of experimental medicine (2016)
An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii-targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ-stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ-mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.
Keyphrases
- gene expression
- immune response
- toxoplasma gondii
- dendritic cells
- transcription factor
- genome wide
- dna methylation
- cell proliferation
- plasmodium falciparum
- toll like receptor
- metabolic syndrome
- patient safety
- adipose tissue
- type diabetes
- induced apoptosis
- liver failure
- cell therapy
- bone marrow
- oxidative stress
- high fat diet induced
- single molecule
- drug delivery
- mesenchymal stem cells
- skeletal muscle
- acute respiratory distress syndrome
- extracorporeal membrane oxygenation