Cited by 178Tuberculosis Research and EpidemiologyInfectious Diseases and TuberculosisDiagnosis and treatment of tuberculosis

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The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis

Krishnan, Nitya, Robertson, Brian D., Thwaites, Guy·2010·Tuberculosis

DOI 10.1016/j.tube.2010.08.005

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Abstract

The dissemination of Mycobacterium tuberculosis from the primary focus of infection is central to the pathogenesis of tuberculosis. Trafficking of bacteria to the regional lymph nodes is essential to the development of a protective T-cell mediated immune response, but bacteria trafficked within the bloodstream can lead to extra-pulmonary dissemination and some of the most devastating clinical consequences of tuberculosis. Yet how M. tuberculosis leaves the lungs is poorly understood. Here, we review the potential pathways and molecular mechanisms behind the dissemination of M. tuberculosis and consider the consequences to both host and bacteria. To disseminate M. tuberculosis must breach the alveolar epithelium and various bacterial factors have been implicated in this process. Heparin binding haemagglutinin adhesin (HBHA) enables M. tuberculosis to bind to sulphated glycoconjugates on epithelial cells; disruption of its synthesis severely impairs the ability of bacteria to disseminate from the lungs to the spleen. Two products of the M. tuberculosis RD1 gene locus, early secretory antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10), have been linked to cell lysis and may enable bacteria to invade and spread within the alveolar epithelium. Recent studies in embryonic zebrafish indicate ESAT-6 may also stimulate the trafficking of infected macrophages within granulomas, thereby promoting the early dissemination of bacteria. These findings challenge conventional notions of the protective role of granulomas in mycobacterial infection and indicate M. tuberculosis has evolved specific mechanisms which utilise granulomas as foci of macrophage recruitment, infection, and subsequent bacterial dissemination. Further understanding of the pathways, mechanisms and consequences of M. tuberculosis dissemination could have a major impact in designing novel vaccines and therapeutic strategies.

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Authors: Krishnan, N., Robertson, B. D., & Thwaites, G.
Affiliations: Imperial College London (GB)
Corresponding author: Krishnan, Nitya
ORCID: Robertson, Brian D.
Thwaites, Guy
Venue: Tuberculosis
Publisher: Elsevier BV
Published: 2010-11
Volume: 90
Issue: 6
Pages: 361-366
ISSN: 1472-9792 (ISSN-L)
DOI: 10.1016/j.tube.2010.08.005
OpenAlex: W2059831659
Cited by: 178
References: 75
Citations by year: 2026: 9 · 2025: 14 · 2024: 12 · 2023: 13 · 2022: 20 · 2021: 8 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 14 · 2016: 15 · 2015: 8 · 2014: 8 · 2013: 7 · 2012: 9
FWCI: 0.72
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Tuberculosis (publishedVersion)
PubMed (publishedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Wellcome Trust
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
Health Sciences › Medicine › Infectious Diseases › Diagnosis and treatment of tuberculosis
Keywords: Mycobacterium tuberculosis, alveolar epithelium, HBHA, ESAT-6, CFP-10, granuloma, macrophage trafficking, spleen, lymph node trafficking, T cell immunity, zebrafish model
MeSH terms: Antigens, Bacterial, Bacterial Proteins, Epithelial Cells, Humans, Lung, Membrane Proteins, Mycobacterium Infections, Mycobacterium tuberculosis, Phagocytes

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The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis

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