1. The UPR sensor IRE1α promotes dendritic cell responses to control Toxoplasma gondii infection
- Author
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Jamal Khalife, Sofie Rennen, Eik Hoffmann, Sophie Janssens, Nicolas Blanchard, Véronique Peucelle, Sabrina Marion, Ludovic Huot, Victor Bosteels, Sandra Maréchal, Anaïs F Poncet, Sylia Chehade, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SM has been supported by the Laboratoire d’Excellence (LabEx) ParaFrap from the National Agency for Research ANR-11-LABX-0024 grant and a joint Chaire d’Excellence from Université of Lille and the Centre National pour la Recherche Scientifique (CNRS). SJ is a recipient of an ERC Consolidator Grant (Grant Number 819314), several FWO program grants and an EOS grant (G0G7318N). VB is holder of an FWO PhD Fellowship and SR received a PhD BOF grant from the University of Ghent., ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Khalife, Jamal, and Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID
- Subjects
Antigen presentation ,Toxoplasma gondii ,UPR ,Protein Serine-Threonine Kinases ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Immunity ,Endoribonucleases ,Genetics ,Medicine and Health Sciences ,Animals ,dendritic cells ,[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,ATF6 ,Biology and Life Sciences ,Articles ,Dendritic cell ,biology.organism_classification ,cytokines ,3. Good health ,antigen presentation ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Immunology ,Unfolded Protein Response ,Cytokine secretion ,Toxoplasma ,Toxoplasmosis ,030217 neurology & neurosurgery - Abstract
The unfolded protein response (UPR) has emerged as a central regulator of immune cell responses in several pathologic contexts including infections. However, how intracellular residing pathogens modulate the UPR in dendritic cells (DCs) and thereby affect T cell-mediated immunity remains uncharacterized. Here, we demonstrate that infection of DCs with Toxoplasma gondii (T. gondii) triggers a unique UPR signature hallmarked by the MyD88-dependent activation of the IRE1 alpha pathway and the inhibition of the ATF6 pathway. Induction of XBP1s controls pro-inflammatory cytokine secretion in infected DCs, while IRE1 alpha promotes MHCI antigen presentation of secreted parasite antigens. In mice, infection leads to a specific activation of the IRE1 alpha pathway, which is restricted to the cDC1 subset. Mice deficient for IRE1 alpha and XBP1 in DCs display a severe susceptibility to T. gondii and succumb during the acute phase of the infection. This early mortality is correlated with increased parasite burden and a defect in splenic T-cell responses. Thus, we identify the IRE1 alpha/XBP1s branch of the UPR as a key regulator of host defense upon T. gondii infection.
- Published
- 2021
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