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* Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, NC 27705;
Department of Medicine,
Department of Molecular Genetics and Microbiology, and
Department of Immunology, Division of Geriatrics and Center for the Study of Aging and Human Development, Duke University Medical Center;
¶ Department of Medicine, Human Vaccine Institute;
|| Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; and
# Department of Pathology, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27705
IRG proteins, or immunity-related GTPases (also known as p47 GTPases), are a group of IFN-regulated proteins that are highly expressed in response to infection. The proteins localize to intracellular membranes including vacuoles that contain pathogens in infected macrophages and other host cells. Current data indicate that the IRG protein Irgm1 (LRG-47) is critical for resistance to intracellular bacteria. This function is thought to be a consequence of regulating the survival of vacuolar bacteria in host cells. In the current work, the role of Irgm1 in controlling resistance to Salmonella typhimurium was explored to further define the mechanism through which the protein regulates host resistance. Irgm1-deficient mice displayed increased susceptibility to this bacterium that was reflected in increased bacterial loads in spleen and liver and decreased maturation of S. typhimurium granulomas. The mice also displayed an inability to concentrate macrophages at sites of bacterial deposition. In vitro, the ability of Irgm1-deficient macrophages to suppress intracellular growth of S. typhimurium was impaired. Furthermore, adhesion and motility of Irgm1-deficient macrophages after activation with IFN-
was markedly decreased. Altered adhesion/motility of those cells was accompanied by changes in cell morphology, density of adhesion-associated proteins, and actin staining. Together, these data suggest that in addition to regulating the maturation of pathogen-containing vacuoles, Irgm1 plays a key role in regulating the adhesion and motility of activated macrophages.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by National Institutes of Health Grant AI57831.
2 Address correspondence and reprint requests to Dr. Gregory A. Taylor, Duke University, Box 3003, Duke University Medical Center, Durham, NC 27710. E-mail address: gregory.taylor{at}duke.edu
3 Abbreviations used in this paper: IRG, immune-regulated GTPase; BMM, bone marrow macrophage; WT, wild type; LDH, lactate dehydrogenase; PMN, polymorphonuclear cell.
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