title: Manipulation of Interleukin-1β and Interleukin-18 Production by Yersinia pestis Effectors YopJ and YopM and Redundant Impact on Virulence.
abstract: Innate immunity plays a central role in resolving infections by pathogens. Host survival during plague, caused by the Gram-negative bacterium Yersinia pestis, is favored by a robust early innate immune response initiated by IL-1β and IL-18. These cytokines are produced by a two-step mechanism involving NF-κB-mediated pro-cytokine production and inflammasome-driven maturation into bioactive inflammatory mediators. Because of the anti-microbial effects induced by IL-1β/IL-18, it may be desirable for pathogens to manipulate their production. Y. pestis type III secretion system effectors YopJ and YopM can interfere with different parts of this process. Both effectors have been reported to influence inflammasome caspase-1 activity; YopJ promotes caspase-8-dependent cell death and caspase-1 cleavage, whereas YopM inhibits caspase-1 activity via an incompletely understood mechanism. However, neither effector appears essential for full virulence in vivo Here we report that the sum of influences by YopJ and YopM on IL-1β/IL-18 release is suppressive. In the absence of YopM, YopJ minimally affects caspase-1 cleavage but suppresses IL-1β, IL-18, and other cytokines and chemokines. Importantly, we find that Y. pestis containing combined deletions of YopJ and YopM induces elevated levels of IL-1β/IL-18 in vitro and in vivo and is significantly attenuated in a mouse model of bubonic plague. The reduced virulence of the YopJ-YopM mutant is dependent on the presence of IL-1β, IL-18, and caspase-1. Thus, we conclude that Y. pestis YopJ and YopM can both exert a tight control of host IL-1β/IL-18 production to benefit the bacteria, resulting in a redundant impact on virulence.
authors.affiliation: From the Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ratner
authors.affiliation: From the Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway, and.
authors.forename: M Pontus A
authors.initials: MP
authors.lastname: Orning
authors.affiliation: From the Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway, and.
authors.forename: Kristian K
authors.initials: KK
authors.lastname: Starheim
authors.affiliation: From the Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Robyn
authors.initials: R
authors.lastname: Marty-Roix
authors.affiliation: the Department of Microbiology and Physiological Systems, University of Massachusetts, Worcester, Massachusetts 01655.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Proulx
authors.affiliation: the Department of Microbiology and Physiological Systems, University of Massachusetts, Worcester, Massachusetts 01655.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Goguen
authors.affiliation: From the Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway, and egil.lien@umassmed.edu.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D014774:Virulence / Q000276:immunology*; D015009:Yersinia Infections / Q000276:immunology* / Q000382:microbiology; D015010:Yersinia pestis / Q000472:pathogenicity*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C109227:YopP protein, Yersinia; C060772:yopM protein, Yersinia
keywords: Yersinia pestis; YopJ; YopM; caspase 1 (CASP1); cell death; inflammasome; interleukin 1 (IL-1); interleukin-18 (IL-18); macrophage; type III secretion system (T3SS)