title: Hijacking of the pleiotropic cytokine interferon-γ by the type III secretion system of Yersinia pestis.
abstract: Yersinia pestis, the causative agent of bubonic plague, employs its type III secretion system to inject toxins into target cells, a crucial step in infection establishment. LcrV is an essential component of the T3SS of Yersinia spp, and is able to associate at the tip of the secretion needle and take part in the translocation of anti-host effector proteins into the eukaryotic cell cytoplasm. Upon cell contact, LcrV is also released into the surrounding medium where it has been shown to block the normal inflammatory response, although details of this mechanism have remained elusive. In this work, we reveal a key aspect of the immunomodulatory function of LcrV by showing that it interacts directly and with nanomolar affinity with the inflammatory cytokine IFNγ. In addition, we generate specific IFNγ mutants that show decreased interaction capabilities towards LcrV, enabling us to map the interaction region to two basic C-terminal clusters of IFNγ. Lastly, we show that the LcrV-IFNγ interaction can be disrupted by a number of inhibitors, some of which display nanomolar affinity. This study thus not only identifies novel potential inhibitors that could be developed for the control of Yersinia-induced infection, but also highlights the diversity of the strategies used by Y. pestis to evade the immune system, with the hijacking of pleiotropic cytokines being a long-range mechanism that potentially plays a key role in the severity of plague.
authors.affiliation: Institut de Biologie Structurale, UMR 5075 (Comissariat à l'Enérgie Atomique/Centre National de la Recherche Scientifique/Université Grenoble I), Grenoble, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gendrin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sarrazin
authors.forename: David
authors.initials: D
authors.lastname: Bonnaffé
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Jault
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000235:genetics; D001974:Bromosuccinimide / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D009154:Mutation; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence / Q000379:methods; D020298:U937 Cells; D015010:Yersinia pestis / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D007371:Interferon-gamma; D005982:Glutathione Transferase; D001974:Bromosuccinimide