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

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

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

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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Crossref · 10.1016/j.tube.2010.08.005

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Authors
Krishnan, N., Robertson, B. D., & Thwaites, G.
Affiliations
Imperial College London (GB)
Corresponding author
Krishnan, Nitya
Venue
Tuberculosis
Publisher
Elsevier BV
Published
2010-11
Volume
90
Issue
6
Pages
361-366
ISSN
1472-9792 (ISSN-L)
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
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 › Surgery › Infectious Diseases and Tuberculosis
  • Health Sciences › Medicine › Surgery › 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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