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. The interaction between immune system and invading bacteria is sufficient to eradicate microorganisms in the majority of bacterial infections, but the suppression of the microbicidal response leads to reactivation or chronic evolution of infections and to bacterial persistence. Coxiella burnetii, an obligate intracellular bacterium, is responsible for Q fever. This infectious disease is characterized by a primary infection that may become chronic as endocarditis in patients with valvular damage and immunocompromised patients. Clinical and in vitro studies have suggested a role for interleukin-10 in the chronic evolution of Q fever. However, an efficient mouse model for chronic Q fever pathogenesis, which could serve as a platform for anti–C. burnetii drug or immunotherapy development, is lacking. Here we use transgenic mice with constitutive overexpression of interleukin-10 in the macrophage lineage to study C. burnetii infection. We report an efficient mouse model for chronic Q fever pathogenesis, which associates high levels of specific antibodies, sustained tissue infection, and reduced granuloma formation, as in human Q fever. We also find an anti-inflammatory transcriptional program and altered expression of chemokines in infected tissues.