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Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids
Open accessAbstract
The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs) promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence, and PGL, which (along with CCR2) is known to be associated with human tuberculosis. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signalling.
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“This is partly explained by its ability to mask pathogen- associated molecular patterns of the cell wall from the innate immune system, enabling M. tuberculosis to recruit naive rather than microbicidal macrophages112.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [112]
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“In addition, phenolic glycolipids promote the recruitment of M. tuberculosis permissive macrophages via stimulation of host chemokine receptor 2 expression, whereas the invasion of TLR responsive microbicidal macrophages producing reactive nitrogen and oxygen species is impaired (6).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [6]
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Metadata
- Authors
- Cambier, C. J., Takaki, K. K., Larson, R. P., Hernandez, R. E., Tobin, D. M., Urdahl, K. B., Cosma, C. L., & Ramakrishnan, L.
- Affiliations
- University of Washington (US)
- Center for Infectious Disease Research (US)
- Corresponding author
- Ramakrishnan, Lalita
- ORCID
- Venue
- Nature
- Published
- 2013-12-15
- Volume
- 505
- Issue
- 7482
- Pages
- 218-222
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3961847
- OpenAlex
- W1977138279
- Cited by
- 480
- References
- 41
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 27 · 2023: 31 · 2022: 35 · 2021: 42 · 2020: 46 · 2019: 42 · 2018: 44 · 2017: 48 · 2016: 44 · 2015: 32 · 2014: 38 · 2013: 2
- FWCI
- 28.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (103950/Z/14/Z)
- National Institutes of Health (DP1OD006782)
- National Institute of Mental Health (DP1MH099901)
- National Institute of Allergy and Infectious Diseases (R01AI076327, R01AI036396, R37AI054503, R01AI054503)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Mycobacterium tuberculosis, Mycobacterium marinum, tuberculosis, macrophage recruitment, immune evasion, phthiocerol dimycocerosate, phenolic glycolipids, pathogen-associated molecular patterns, Toll-like receptor signaling, reactive nitrogen species, bacterial membrane lipids, host-pathogen interaction, zebrafish
- MeSH terms
- Animals, Female, Glycolipids, Lipids, Macrophages, Membrane Lipids, Mice, Inbred C57BL, Mycobacterium, Mycobacterium tuberculosis, Virulence, Zebrafish, Toll-Like Receptors, Mice, Receptors, CCR2, Immune Evasion
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