Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis
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ABSTRACT: A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after coinfection with Mycobacterium tuberculosis and Th2 eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow derived macrophages alternatively activated by IL-4 to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4 and IFN-g activated macrophages revealed delayed and partially diminished responses in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively, to intracellular bacteria. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bfrB as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix remodelling enzyme matrix metalloproteinase-12 (MMP-12) was induced in alternatively activated macrophages in vitro, and MMP-12 expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms which limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis. Keywords: transcriptome, gene regulation, macrophages, IL-4, IFN-gamma, nitric oxide
ORGANISM(S): Mus musculus
PROVIDER: GSE3552 | GEO | 2006/01/01
SECONDARY ACCESSION(S): PRJNA93625
REPOSITORIES: GEO
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