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

PLoS Pathogens

Amandine Martin¹  Fanny Michal¹  Angelina Provost¹  Amandine Mosnier¹  Bénédicte F. Py¹  Thomas Henry¹  Pierre Wallet¹  Sacha Benaoudia¹  Sophia Djebali¹  Brice Lagrange¹  Omran Allatif¹  Masahiro Yamamoto²  Petr Broz³  Etienne Meunier⁴  Igor Golovliov⁵  Anders Sjöstedt⁵  Helena Lindgren⁵  Eric Faudry⁶  Pauline Basso⁶ 

[1] CIRI, Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, Lyon, France;Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland;Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, Université Paul Sabatier (UPS), Toulouse, France;Laboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Umeå University, Umeå, Sweden;University of Grenoble Alpes, CNRS, ERL5261, CEA, BIG-BCI, Inserm, U1036, Grenoble, France

关键词: Inflammasomes;    Macrophages;    Apoptosis;    Cell death;    Iodides;    Francisella tularensis;    Antibacterials;    Intracellular pathogens;   

DOI  :  10.1371/journal.ppat.1006630

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY