Human Toll-Like Receptors Mediate Cellular Activation by Mycobacterium tuberculosis
Open accessAbstract
Recent studies have implicated a family of mammalian Toll-like receptors (TLR) in the activation of macrophages by Gram-negative and Gram-positive bacterial products. We have previously shown that different TLR proteins mediate cellular activation by the distinct CD14 ligands Gram-negative bacterial LPS and mycobacterial glycolipid lipoarabinomannan (LAM). Here we show that viable Mycobacterium tuberculosis bacilli activated both Chinese hamster ovary cells and murine macrophages that overexpressed either TLR2 or TLR4. This contrasted with Gram-positive bacteria and Mycobacterium avium, which activated cells via TLR2 but not TLR4. Both virulent and attenuated strains of M. tuberculosis could activate the cells in a TLR-dependent manner. Neither membrane-bound nor soluble CD14 was required for bacilli to activate cells in a TLR-dependent manner. We also assessed whether LAM was the mycobacterial cell wall component responsible for TLR-dependent cellular activation by M. tuberculosis. We found that TLR2, but not TLR4, could confer responsiveness to LAM isolated from rapidly growing mycobacteria. In contrast, LAM isolated from M. tuberculosis or Mycobacterium bovis bacillus Calmette-Guérin failed to induce TLR-dependent activation. Lastly, both soluble and cell wall-associated mycobacterial factors were capable of mediating activation via distinct TLR proteins. A soluble heat-stable and protease-resistant factor was found to mediate TLR2-dependent activation, whereas a heat-sensitive cell-associated mycobacterial factor mediated TLR4-dependent activation. Together, our data demonstrate that Toll-like receptors can mediate cellular activation by M. tuberculosis via CD14-independent ligands that are distinct from the mycobacterial cell wall glycolipid LAM.
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Mycobacterium tuberculosis signals mainly through TLR 2, 6, and 9.
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Means et al., 1999
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- Authors
- Means, T. K., Wang, S., Lien, E., Yoshimura, A., Golenbock, D. T., & Fenton, M. J.
- Affiliations
- Boston University (US)
- Boston Medical Center (US)
- Corresponding author
- Wang, Shuyan
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-10-01
- Volume
- 163
- Issue
- 7
- Pages
- 3920-3927
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2102578857
- Cited by
- 804
- References
- 35
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 13 · 2020: 10 · 2019: 9 · 2018: 17 · 2017: 17 · 2016: 16 · 2015: 25 · 2014: 33 · 2013: 37 · 2012: 37
- FWCI
- 19.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Immunology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Kreftforeningen
- Norges Forskningsråd
- National Institutes of Health (5r01hl055681-05, GM54060)
- National Heart, Lung, and Blood Institute (HL55681)
- National Institute of General Medical Sciences (GM 54060)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Toll-like receptors, Mycobacterium tuberculosis, TLR2, TLR4, lipoarabinomannan, macrophage activation, heat-stable factor, BCG, Mycobacterium avium, bacterial virulence
- MeSH terms
- Lipopolysaccharide-Binding Protein, Acute-Phase Proteins, Animals, Bacterial Proteins, Carrier Proteins, Cell Line, Fibroblasts, Cricetinae, Humans, Lipopolysaccharides, Macrophage Activation, Mannans, Membrane Glycoproteins, Mycobacterium tuberculosis, Receptors, Cell Surface, Solubility, CHO Cells, Lipopolysaccharide Receptors, Drosophila Proteins, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice
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