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      Biomarkers for tuberculosis: the case for lipoarabinomannan

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          Abstract

          Tuberculosis (TB) is considered the most onerous of infectious diseases according to recent reports from the World Health Organization. Available tests for TB diagnosis present severe limitations, and a reliable point-of-care (POC) diagnostic test does not exist. Neither is there a test to discern between the different stages of TB, and in particular to predict which patients with Mycobacterium tuberculosis infection and no clinical signs are more at risk of advancing to overt disease. We here review the usefulness of mycobacterial lipoarabinomannan (LAM) as a diagnostic marker for active and latent TB and, also, aspects of the immune response to LAM relevant to such tests. There is a high potential for urinary LAM-based POC tests for the diagnosis of active TB. Some technical challenges to optimised sensitivity of the test will be detailed. A method to quantify LAM in urine or serum should be further explored as a test of treatment effect. Recent data on the immune response to LAM suggest that markers for host response to LAM should be investigated for a prognostic test to recognise individuals at the greatest risk of disease activation.

          Abstract

          There is a high potential for a urinary LAM-based point-of-care test to diagnose TB. Markers for host response to LAM should be explored to identify those at highest risk of developing active TB. http://ow.ly/FyCs30n4uFE

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          Most cited references95

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          A Functional Role for Antibodies in Tuberculosis.

          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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            Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial.

            HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.
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              Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.

              Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n(-/-) BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n(-/-) mice were resistant. Upon mycobacterial infection, Clec4n(-/-) mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                ERJ Open Res
                ERJ Open Res
                ERJOR
                erjor
                ERJ Open Research
                European Respiratory Society
                2312-0541
                February 2019
                11 February 2019
                : 5
                : 1
                : 00115-2018
                Affiliations
                [1 ]Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
                [2 ]ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
                [3 ]Division of Infectious Diseases, Dept of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
                [4 ]Dept of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
                [5 ]Biopromic AB, Solna, Sweden
                [6 ]Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique
                [7 ]Fundação Ariel Glaser Contra o SIDA Pediátrico, Maputo, Mozambique
                [8 ]Dept of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
                [9 ]Dept of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
                Author notes
                Gunilla Källenius, Division of Infectious Diseases, Dept of Medicine Solna, Karolinska Institutet, Stockholm 17176, Sweden. E-mail: gunilla.kallenius@ 123456ki.se
                Author information
                https://orcid.org/0000-0002-0551-0072
                https://orcid.org/0000-0002-8921-0551
                Article
                00115-2018
                10.1183/23120541.00115-2018
                6368998
                30775376
                5f170caf-acf6-4108-b7b8-80d4a4a6f43e
                Copyright ©ERS 2019

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 20 July 2018
                : 05 November 2018
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