8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Investigating Non-sterilizing Cure in TB Patients at the End of Successful Anti-TB Therapy

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mycobacterium tuberculosis (Mtb) is extremely recalcitrant to antimicrobial chemotherapy requiring 6 months to treat drug-sensitive tuberculosis (TB). Despite this, 4–10% of cured patients will develop recurrent disease within 12 months after completing therapy. Reasons for relapse in cured TB patients remains speculative, attributed to both pathogen and host factors. Populations of dormant bacilli are hypothesized to cause relapse in initially cured TB patients however, development of tests to convincingly demonstrate their presence at the end of anti-TB treatment has been challenging. Previous studies have indicated the utility of culture filtrate supplemented media (CFSM) to detect differentially culturable tubercle bacilli (DCTB). Here, we show that 3/22 of clinically cured patients retained DCTB in induced sputum and bronchoalveolar lavage fluid (BALF), with one DCTB positive patient relapsing within the first year of completing therapy. We also show a correlation of DCTB status with “unresolved” end of treatment FDG PET-CT imaging. Additionally, 19 end of treatment induced sputum samples from patients not undergoing bronchoscopy were assessed for DCTB, identifying a further relapse case with DCTB. We further show that induced sputum is a less reliable source for the DCTB assay at the end of treatment, limiting the utility of this assay in a clinical setting. We next investigated the host proteome at the site of disease (BALF) using multiplexed proteomic analysis and compared these to active TB cases to identify host-specific factors indicative of cure. Distinct signatures stratified active from cured TB patients into distinct groups, with a DCTB positive, subsequently relapsing, end of treatment patient showing a proteomic signature closer to active TB disease than cure. This exploratory study offers evidence of live Mtb, undetectable with conventional culture methods, at the end of clinically successful treatment and putative host protein biomarkers of active disease and cure. These findings have implications for the assessment of true sterilizing cure in TB patients and opens new avenues for targeted approaches to monitor treatment response.

          Related collections

          Most cited references33

          • Record: found
          • Abstract: found
          • Article: not found

          Bacterial persistence as a phenotypic switch.

          A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microfluidic devices. Persistence was linked to preexisting heterogeneity in bacterial populations because phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates. Quantitative measurements led to a simple mathematical description of the persistence switch. Inherent heterogeneity of bacterial populations may be important in adaptation to fluctuating environments and in the persistence of bacterial infections.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mycobacterium tuberculosis: success through dormancy.

            Tuberculosis (TB) remains a major health threat, killing nearly 2 million individuals around this globe, annually. The only vaccine, developed almost a century ago, provides limited protection only during childhood. After decades without the introduction of new antibiotics, several candidates are currently undergoing clinical investigation. Curing TB requires prolonged combination of chemotherapy with several drugs. Moreover, monitoring the success of therapy is questionable owing to the lack of reliable biomarkers. To substantially improve the situation, a detailed understanding of the cross-talk between human host and the pathogen Mycobacterium tuberculosis (Mtb) is vital. Principally, the enormous success of Mtb is based on three capacities: first, reprogramming of macrophages after primary infection/phagocytosis to prevent its own destruction; second, initiating the formation of well-organized granulomas, comprising different immune cells to create a confined environment for the host-pathogen standoff; third, the capability to shut down its own central metabolism, terminate replication, and thereby transit into a stage of dormancy rendering itself extremely resistant to host defense and drug treatment. Here, we review the molecular mechanisms underlying these processes, draw conclusions in a working model of mycobacterial dormancy, and highlight gaps in our understanding to be addressed in future research. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Acute-phase proteins: As diagnostic tool

              The varied reactions of the host to infection, inflammation, or trauma are collectively known as the acute-phase response and encompass a wide range of pathophysiological responses such as pyrexia, leukocytosis, hormone alterations, and muscle protein depletion combining to minimize tissue damage while enhancing the repair process. The mechanism for stimulation of hepatic production of acute-phase proteins is by proinflammatory cytokines. The functions of positive acute-phase proteins (APP) are regarded as important in optimization and trapping of microorganism and their products, in activating the complement system, in binding cellular remnants like nuclear fractions, in neutralizing enzymes, scavenging free hemoglobin and radicals, and in modulating the host’s immune response. APP can be used as diagnostic tool in many diseases like bovine respiratory syncytial virus, prostate cancer, bronchopneumonia, multiple myeloma, mastitis, Streptococcus suis infection, starvation, or lymphatic neoplasia. Thus, acute-phase proteins may provide an alternative means of monitoring animal health.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                25 August 2020
                2020
                : 10
                : 443
                Affiliations
                [1] 1Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research , Cape Town, South Africa
                [2] 2Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town, South Africa
                [3] 3Faculty of Medical Sciences, Biosciences Institute, Newcastle University , Newcastle upon Tyne, United Kingdom
                [4] 4Section Molecular Microbiology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam , Amsterdam, Netherlands
                [5] 5Catalysis Foundation for Health , San Ramon, CA, United States
                [6] 6DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service , Johannesburg, South Africa
                [7] 7MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Centre for the AIDS Programme of Research in South Africa, CAPRISA , Durban, South Africa
                Author notes

                Edited by: Alexandra Aubry, Sorbonne Universités, France

                Reviewed by: Nicolas Veziris, Assistance Publique Hopitaux De Paris, France; Babak Javid, Tsinghua University, China

                *Correspondence: Caroline G. G. Beltran cbeltran@ 123456sun.ac.za

                This article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2020.00443
                7477326
                32984071
                c6a3eca2-9ee6-4858-bbda-b013227d021c
                Copyright © 2020 Beltran, Heunis, Gallant, Venter, du Plessis, Loxton, Trost, Winter, Malherbe, Kana and Walzl.

                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) and the copyright owner(s) 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
                : 13 May 2020
                : 20 July 2020
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 53, Pages: 14, Words: 10052
                Funding
                Funded by: South African Medical Research Council 10.13039/501100001322
                Categories
                Cellular and Infection Microbiology
                Original Research

                Infectious disease & Microbiology
                tuberculosis,sterilizing cure,mycobacterium tuberculosis,differentially culturable tubercle bacteria,dormant,18f-fdg pet-ct,balf proteome analysis,treatment response

                Comments

                Comment on this article