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      Modeling the Mycobacterium tuberculosis Granuloma – the Critical Battlefield in Host Immunity and Disease

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          Abstract

          Granulomas are the hallmark of Mycobacterium tuberculosis ( M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis. TB can result from either early progression of a primary granuloma during the infection process or reactivation of an established granuloma in a latently infected person. Granulomas are compact, organized aggregates of immune cells consisting of blood-derived infected and uninfected macrophages, foamy macrophages, epithelioid cells (uniquely differentiated macrophages), and multinucleated giant cells (Langerhans cells) surrounded by a ring of lymphocytes. The granuloma’s main function is to localize and contain M.tb while concentrating the immune response to a limited area. However, complete eradication does not occur since M.tb has its own strategies to persist within the granuloma and to reactivate and escape under certain conditions. Thus M.tb-containing granulomas represent a unique battlefield for dictating both the host immune and bacterial response. The architecture, composition, function, and maintenance of granulomas are key aspects to study since they are expected to have a profound influence on M.tb physiology in this niche. Granulomas are not only present in mycobacterial infections; they can be found in many other infectious and non-infectious diseases and play a crucial role in immunity and disease. Here we review the models currently available to study the granulomatous response to M.tb.

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          Revisiting the role of the granuloma in tuberculosis.

          The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries--from imaging studies coupled with genetic manipulations--that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases.
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            The role of the granuloma in expansion and dissemination of early tuberculous infection.

            Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection. Intracellular mycobacteria use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary granuloma then seeds secondary granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the granuloma during the innate immune phase for local expansion and systemic dissemination.
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              The continuing challenges of leprosy.

              Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. The second is a peripheral neuropathy that is initiated by the infection and the accompanying immunological events. The infection is curable but not preventable, and leprosy remains a major global health problem, especially in the developing world, publicity to the contrary notwithstanding. Mycobacterium leprae remains noncultivable, and for over a century leprosy has presented major challenges in the fields of microbiology, pathology, immunology, and genetics; it continues to do so today. This review focuses on recent advances in our understanding of M. leprae and the host response to it, especially concerning molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis. Advances in experimental models include studies in gene knockout mice and the development of molecular techniques to explore the armadillo model. In clinical studies, notable progress has been made concerning the immunology and immunopathology of leprosy, the genetics of human resistance, mechanisms of nerve injury, and chemotherapy. In nearly all of these areas, however, leprosy remains poorly understood compared to other major bacterial diseases.
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                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                22 April 2013
                2013
                : 4
                : 98
                Affiliations
                [1] 1Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University Columbus, OH, USA
                Author notes

                Edited by: Stephen Wesley Chensue, University of Michigan, USA

                Reviewed by: Raphaela Goldbach-Mansky, National Institutes of Health, USA; Dennis D. Taub, National Institute on Aging, USA

                *Correspondence: Larry S. Schlesinger, Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, 460 West, 12th Avenue, Room 1004, Columbus, OH 43210, USA. e-mail: larry.schlesinger@ 123456osumc.edu

                This article was submitted to Frontiers in Inflammation, a specialty of Frontiers in Immunology.

                Article
                10.3389/fimmu.2013.00098
                3631743
                23626591
                03f2c4d5-42bf-414f-8f84-04de7fc394b1
                Copyright © 2013 Guirado and Schlesinger.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 07 November 2012
                : 11 April 2013
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 71, Pages: 7, Words: 6519
                Categories
                Immunology
                Mini Review

                Immunology
                mycobacterium tuberculosis,model,granuloma,tuberculosis,pathogenesis
                Immunology
                mycobacterium tuberculosis, model, granuloma, tuberculosis, pathogenesis

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