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.
Highlights
The interaction between innate/adaptive immune system and invading bacteria is sufficient to eradicate microorganisms in the majority of bacterial infections
At day 28 post-infection, only residual organ bacterial levels were observed in wt mice, whereas the infection of spleen, liver, and lungs was persistent in macIL-10tg mice, for the lungs (p, 0.05)
IL-10 overexpression was associated with sustained presence of C. burnetii in tissues and high levels of specific Abs, which was reminiscent of chronic Q fever
Summary
The interaction between innate/adaptive immune system and invading bacteria is sufficient to eradicate microorganisms in the majority of bacterial infections. This microbicidal response is based on inflammatory cytokines, such as interferon (IFN)-c and tumor necrosis factor (TNF), which control the expression of cytokines and chemokines and the production of toxic metabolites [1]. Immunosuppressive treatments and anti-inflammatory cytokines such as interleukin (IL)-10 or transforming growth factor (TGF)-b may disarm microbicidal responses and contribute to chronic evolution of bacterial infectious diseases [1,3]. Coxiella burnetii is an obligate intracellular bacterium that replicates in macrophages (M/) and is responsible for Q fever. IL-10 blocks maturation of C. burnetii–containing phagosomes in monocytes from patients with Q fever endocarditis [11]
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