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Cited by 238Tuberculosis Research and EpidemiologyImmune responses and vaccinationsImmune Response and Inflammation

Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule

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Rao, Vivek, Fujiwara, Nagatoshi, Porcelli, Steven A., Glickman, Michael S.·2005·The Journal of Experimental Medicine
DOI 10.1084/jem.20041668PMC PMC2213067
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Abstract

Mycobacterium tuberculosis (Mtb) infection remains a global health crisis. Recent genetic evidence implicates specific cell envelope lipids in Mtb pathogenesis, but it is unclear whether these cell envelope compounds affect pathogenesis through a structural role in the cell wall or as pathogenesis effectors that interact directly with host cells. Here we show that cyclopropane modification of the Mtb cell envelope glycolipid trehalose dimycolate (TDM) is critical for Mtb growth during the first week of infection in mice. In addition, TDM modification by the cyclopropane synthase pcaA was both necessary and sufficient for proinflammatory activation of macrophages during early infection. Purified TDM isolated from a cyclopropane-deficient pcaA mutant was hypoinflammatory for macrophages and induced less severe granulomatous inflammation in mice, demonstrating that the fine structure of this glycolipid was critical to its proinflammatory activity. These results established the fine structure of lipids contained in the Mtb cell envelope as direct effectors of pathogenesis and identified temporal control of host immune activation through cyclopropane modification of TDM as a critical pathogenic strategy of Mtb.

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  • pcaA is transcriptionally upregulated in the active phase, and blocks phagosome-lysosome fusion and stimulation of the pro-inflammatory cytokine tumour necrosis factor in macrophage infections, which implies that cis cyclopropanations are important for early stages of infection.

    “pcaA is transcriptionally upregulated in the active phase60, and blocks phagosome–lysosome fusion96 and stimulation of the pro-​inflammatory cytokine tumour necrosis factor in macrophage infections97, which implies that cis cyclopropanations are impor- tant for early stages of infection.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [97]

    Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • PcaA is a cyclopropane synthase that adds the proximal cis-cyclopropanes of cis/cis-meromycolates.

    “PcaA is a cyclopropane synthase that adds the proximal cis-​cyclopropanes of cis/cis-​meromycolates96,97”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [97]

    The paper’s Abstract identifies pcaA as encoding an enzyme that catalyzes proximal cyclopropanation of α-mycolate, and the Results section reports that α-mycolates in ΔpcaA TDM lack a cyclopropyl ring. Our copy does not specify that the rings are cis-cyclopropanes on cis/cis-meromycolates. No page numbers are provided in the indexed copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These modifications reduce tumour necrosis factor stimulation and virulence; that is, they have the opposite effect of cis cyclopropanations.

    “These mod- ifications reduce tumour necrosis factor stimulation and virulence100; that is, they have the opposite effect of cis cyclopropanations97.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [97]

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References 48 · Cited by 238

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Authors
Rao, V., Fujiwara, N., Porcelli, S. A., & Glickman, M. S.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Albert Einstein College of Medicine (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2005-02-14
Volume
201
Issue
4
Pages
535-543
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20041668
PMC
PMC2213067
OpenAlex
W2139360890
Cited by
238
References
48
Citations by year
2026: 1 · 2025: 8 · 2024: 5 · 2023: 3 · 2022: 8 · 2021: 9 · 2020: 9 · 2019: 16 · 2018: 7 · 2017: 16 · 2016: 10 · 2015: 10 · 2014: 15 · 2013: 14 · 2012: 16
FWCI
11.56
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI053417, AI53417, R01AI048933, AI45889, R01AI045889, AI-48933)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
Mycobacterium tuberculosis, trehalose dimycolate, macrophage activation, innate immune activation, granulomatous inflammation, bacterial pathogenesis, host-pathogen interaction
MeSH terms
Animals, Cell Line, Cord Factors, Cyclopropanes, Immunity, Innate, Macrophage Activation, Macrophages, Methyltransferases, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Tuberculosis, Pulmonary, Tumor Necrosis Factor-alpha, Colony Count, Microbial, Interleukin-6, Mice, Knockout, Mice

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