IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Pierre Wallet (1) , Sacha Benaoudia (1) , Amandine Mosnier (2) , Brice Lagrange (1) , Amandine Martin (1) , Helena Lindgren (3) , Igor Golovliov (3) , Fanny Michal (1) , Pauline Basso (4) , Sophia Djebali (5) , Angelina Provost (1) , Omran Allatif (6) , Etienne Meunier (7) , Petr Broz (8) , Masahiro Yamamoto (9) , Bénédicte F. Py (10) , Eric Faudry (4) , Anders Sjöstedt (3) , Thomas Henry (1)

1 I2BA - Inflammasome, Infections bactériennes et autoinflammation ; Inflammasome, Bacterial Infections and Autoinflammation [CIRI]
2 Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination [CIRI]
3 Laboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology
4 PBRC - Pathogenèse bactérienne et réponses cellulaires
5 Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes [CIRI]
6 CIRI - Centre International de Recherche en Infectiologie
7 Pathogénie bactérienne et réponses cellulaires
8 Biozentrum [Basel, Suisse]
9 RIMD - Research Institute for Microbial Diseases [Osaka, Japan]
10 Inflammasome NLRP3 – NLRP3 Inflammasome [CIRI]

Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners.

Mots clés: Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Male; Mice; Inbred C57BL; Knockout; Tularemia; Gram-Negative Bacterial Infections; Gene Knockdown Techniques; Francisella tularensis; Francisella; Fluorescent Antibody Technique; Inflammasomes; Interferon-gamma; Immunoblotting; GTP-Binding Proteins; Animals; Disease Models; Animal

Domaines: Immunologie; Bactériologie; Virologie

Pierre Wallet, Sacha Benaoudia, Amandine Mosnier, Brice Lagrange, Amandine Martin, et al.. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection. PLoS Pathogens, 2017, 13 (10), pp.e1006630. ⟨10.1371/journal.ppat.1006630⟩. ⟨hal-01911420⟩