title: Persistent Coxiella burnetii infection in mice overexpressing IL-10: an efficient model for chronic Q fever pathogenesis.
abstract: Interleukin (IL)-10 increases host susceptibility to microorganisms and is involved in intracellular persistence of bacterial pathogens. IL-10 is associated with chronic Q fever, an infectious disease due to the intracellular bacterium Coxiella burnetii. Nevertheless, accurate animal models of chronic C. burnetii infection are lacking. Transgenic mice constitutively expressing IL-10 in macrophages were infected with C. burnetti by intraperitoneal and intratracheal routes and infection was analyzed through real-time PCR and antibody production. Transgenic mice exhibited sustained tissue infection and strong antibody response in contrast to wild-type mice; thus, bacterial persistence was IL-10-dependent as in chronic Q fever. The number of granulomas was low in spleen and liver of transgenic mice infected through the intraperitoneal route, as in patients with chronic Q fever. Macrophages from transgenic mice were unable to kill C. burnetii. C. burnetii-stimulated macrophages were characterized by non-microbicidal transcriptional program consisting of increased expression of arginase-1, mannose receptor, and Ym1/2, in contrast to wild-type macrophages in which expression of inducible NO synthase and inflammatory cytokines was increased. In vivo results emphasized macrophage data. In spleen and liver of transgenic mice infected with C. burnetii by the intraperitoneal route, the expression of arginase-1 was increased while microbicidal pathway consisting of IL-12p40, IL-23p19, and inducible NO synthase was depressed. The overexpression of IL-10 in macrophages prevents anti-infectious competence of host, including the ability to mount granulomatous response and microbicidal pathway in tissues. To our knowledge, this is the first efficient model for chronic Q fever pathogenesis.
authors.affiliation: Unité des Rickettsies, CNRS UMR 6020, Institut Fédératif de Recherche 48, Université de la Méditerranée, Faculté de Médecine, Marseille, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Meghari
authors.forename: Yassina
authors.initials: Y
authors.lastname: Bechah
authors.forename: Christian
authors.initials: C
authors.lastname: Capo
authors.forename: Hubert
authors.initials: H
authors.lastname: Lepidi
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D016997:Coxiella burnetii / Q000472:pathogenicity / Q000502:physiology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006099:Granuloma / Q000382:microbiology / Q000473:pathology; D054884:Host-Pathogen Interactions; D016753:Interleukin-10 / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011778:Q Fever / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000382:microbiology / Q000473:pathology
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D016753:Interleukin-10; C079109:N-(3-pyridylmethyl)adriamycin; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; D001119:Arginase