title: Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF.
abstract: Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF.
authors.affiliation: Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Olleros
authors.affiliation: Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland Laboratory of Integrative Immunology, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Leslie
authors.initials: L
authors.lastname: Chavez-Galan
authors.affiliation: University of Orleans and CNRS, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Noria
authors.initials: N
authors.lastname: Segueni
authors.affiliation: University of Orleans and CNRS, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Bourigault
authors.affiliation: Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Vesin
authors.affiliation: Belozersky Institute of Physico-Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany Laboratory of Experimental Immunology, Lobachevsky State University of Nizhni Novgorod, Nizhni Novgorod, Russia.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Kruglov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Drutskaya
authors.affiliation: Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bisig
authors.affiliation: Priority Research Area Infections, Research Center Borstel, Borstel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.affiliation: Priority Research Area Infections, Research Center Borstel, Borstel, Germany.
authors.forename: Sahar
authors.initials: S
authors.lastname: Aly
authors.affiliation: German Center for Infection Research, Thematic Translational Unit Tuberculosis, Braunschweig, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Walter
authors.affiliation: Laboratory of Experimental Immunology, Lobachevsky State University of Nizhni Novgorod, Nizhni Novgorod, Russia Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kuprash
authors.affiliation: BulBio-National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.
authors.forename: Miliana
authors.initials: M
authors.lastname: Chouchkova
authors.affiliation: Center for Advanced Preclinical Research, Laboratory Animal Sciences Program, Leidos Biomed, Inc., Frederick, Maryland, USA.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kozlov
authors.affiliation: University of Orleans and CNRS, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: François
authors.initials: F
authors.lastname: Erard
authors.affiliation: University of Orleans and CNRS, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: University of Orleans and CNRS, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.affiliation: Belozersky Institute of Physico-Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany Laboratory of Experimental Immunology, Lobachevsky State University of Nizhni Novgorod, Nizhni Novgorod, Russia Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Geneva, Switzerland Irene.garcia-gabay@unige.ch.
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha