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      Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection.

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          Abstract

          Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals 'resisters'. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.

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          Alveolar macrophages: plasticity in a tissue-specific context.

          Tracy Hussell, Thomas Bell (2014)
          Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.
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            Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway.

            Robert O. Watson, Paolo S. Manzanillo, Jeffery S. Cox (2012)
            Eukaryotic cells sterilize the cytosol by using autophagy to route invading bacterial pathogens to the lysosome. During macrophage infection with Mycobacterium tuberculosis, a vacuolar pathogen, exogenous induction of autophagy can limit replication, but the mechanism of autophagy targeting and its role in natural infection remain unclear. Here we show that phagosomal permeabilization mediated by the bacterial ESX-1 secretion system allows cytosolic components of the ubiquitin-mediated autophagy pathway access to phagosomal M. tuberculosis. Recognition of extracelluar bacterial DNA by the STING-dependent cytosolic pathway is required for marking bacteria with ubiquitin, and delivery of bacilli to autophagosomes requires the ubiquitin-autophagy receptors p62 and NDP52 and the DNA-responsive kinase TBK1. Remarkably, mice with monocytes incapable of delivering bacilli to the autophagy pathway are extremely susceptible to infection. Our results reveal an unexpected link between DNA sensing, innate immunity, and autophagy and indicate a major role for this autophagy pathway in resistance to M. tuberculosis infection. Copyright © 2012 Elsevier Inc. All rights reserved.
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              A Functional Role for Antibodies in Tuberculosis.

              Lenette L Lu, Amy W. Chung, Tracy R Rosebrock … (2016)
              While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat Rev Immunol
                Title: Nature reviews. Immunology
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 1474-1741
                ISSN (Print): 1474-1733
                Publication date (Electronic): September 2018
                Volume: 18
                Issue: 9
                Affiliations
                [1 ] Department of Medicine, University of Washington, Seattle, WA, USA. jasonds@uw.edu.
                [2 ] Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
                [3 ] Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
                [4 ] Department of Medicine, University of Washington, Seattle, WA, USA.
                [5 ] Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
                [6 ] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.
                [7 ] Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada.
                [8 ] The Aurum Institute, Parktown, South Africa.
                [9 ] Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
                Article
                Publisher Item ID: 10.1038/s41577-018-0025-3 Mid ID: NIHMS995748
                DOI: 10.1038/s41577-018-0025-3
                PMC ID: 6278832
                PubMed ID: 29895826
                SO-VID: a6d39fa8-c59f-4988-9876-cb87304af18f
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