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      Striking the Right Balance Determines TB or Not TB

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          Abstract

          Mycobacterium tuberculosis continues to be one of the most successful pathogens on earth. Upon inhalation of M. tuberculosis by a healthy individual, the host immune system will attempt to eliminate these pathogens using a combination of immune defense strategies. These include the recruitment of macrophages and other phagocytes to the site of infection, production of cytokines that enhance the microbicidal capacity of the macrophages, as well as the activation of distinct subsets of leukocytes that work in concert to fight the infection. However, being as successful as it is, M. tuberculosis has evolved numerous strategies to subvert host immunity at virtual every level. As a consequence, one third of the world inhabitants carry M. tuberculosis, and tuberculosis continuous to cause disease in more than 8 million people with deadly consequences in well over 1 million patients each year. In this review, we discuss several of the strategies that M. tuberculosis employs to circumvent host immunity, as well as describe some of the mechanisms that the host uses to counter such subversive strategies. As for many other infectious diseases, the ultimate outcome is usually defined by the relative strength of the virulence strategies employed by the tubercle bacillus versus the arsenal of immune defense mechanisms of the infected host.

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          Most cited references154

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          RGD and other recognition sequences for integrins.

          Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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            The inflammasome: an integrated view.

            An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1β (IL-1β). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1β necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1β. This event renders the cell competent for NLRP3 inflammasome activation and IL-1β secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions. © 2011 John Wiley & Sons A/S.
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              Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence.

              I. Smith (2003)
              Tuberculosis (TB), one of the oldest known human diseases. is still is one of the major causes of mortality, since two million people die each year from this malady. TB has many manifestations, affecting bone, the central nervous system, and many other organ systems, but it is primarily a pulmonary disease that is initiated by the deposition of Mycobacterium tuberculosis, contained in aerosol droplets, onto lung alveolar surfaces. From this point, the progression of the disease can have several outcomes, determined largely by the response of the host immune system. The efficacy of this response is affected by intrinsic factors such as the genetics of the immune system as well as extrinsic factors, e.g., insults to the immune system and the nutritional and physiological state of the host. In addition, the pathogen may play a role in disease progression since some M. tuberculosis strains are reportedly more virulent than others, as defined by increased transmissibility as well as being associated with higher morbidity and mortality in infected individuals. Despite the widespread use of an attenuated live vaccine and several antibiotics, there is more TB than ever before, requiring new vaccines and drugs and more specific and rapid diagnostics. Researchers are utilizing information obtained from the complete sequence of the M. tuberculosis genome and from new genetic and physiological methods to identify targets in M. tuberculosis that will aid in the development of these sorely needed antitubercular agents.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                08 October 2014
                2014
                : 5
                : 455
                Affiliations
                [1] 1Biozentrum, University of Basel , Basel, Switzerland
                Author notes

                Edited by: Vishwanath Venketaraman, Western University of Health Sciences, USA

                Reviewed by: Catharine Bosio, National Institutes of Health, USA; Heinrich Korner, Menzies Research Institute Tasmania, Australia

                *Correspondence: Jean Pieters, Biozentrum, University of Basel, Klingelbergstrasse 50-70, Basel CH-4056, Switzerland e-mail: jean.pieters@ 123456unibas.ch

                Present address: Somdeb BoseDasgupta, School of Biomedical Engineering, Indian Institute of Technology (BHU), Varanasi, India

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00455
                4189424
                0c708ede-2a69-4f5f-b932-a29897cf72c6
                Copyright © 2014 BoseDasgupta and Pieters.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 May 2014
                : 06 September 2014
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 200, Pages: 9, Words: 9497
                Categories
                Immunology
                Review Article

                Immunology
                mycobacterium tuberculosis,macrophage,immunity,inflammation
                Immunology
                mycobacterium tuberculosis, macrophage, immunity, inflammation

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