Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Trans -cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis –induced inflammation and virulence
Vivek Rao, … , William R. Jacobs, Michael S. Glickman
Vivek Rao, … , William R. Jacobs, Michael S. Glickman
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1660-1667. https://doi.org/10.1172/JCI27335.
View: Text | PDF
Research Article Microbiology

Trans -cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis –induced inflammation and virulence

  • Text
  • PDF
Abstract

Recent studies have shown that fine structural modifications of Mycobacterium tuberculosis cell envelope lipids mediate host cell immune activation during infection. One such alteration in lipid structure is cis-cyclopropane modification of the mycolic acids on trehalose dimycolate (TDM) mediated by proximal cyclopropane synthase of α mycolates (pcaA), a proinflammatory lipid modification during early infection. Here we examine the pathogenetic role and immunomodulatory function of mycolic acid cyclopropane stereochemistry by characterizing an M. tuberculosis cyclopropane–mycolic acid synthase 2 (cmaA2) null mutant (ΔcmaA2) that lacks trans-cyclopropanation of mycolic acids. Although titers of WT and ΔcmaA2 organisms were identical during mouse infection, ΔcmaA2 bacteria were hypervirulent while inducing larger granulomas than WT M. tuberculosis. The hypervirulence of the ΔcmaA2 strain depended on host TNF-α and IFN-γ. Loss of trans-cyclopropanation enhanced M. tuberculosis–induced macrophage inflammatory responses, a phenotype that was transferable with petroleum ether extractable lipids. Finally, purified TDM lacking trans-cyclopropane rings was 5-fold more potent in stimulating macrophages. These results establish cmaA2-dependent trans-cyclopropanation of TDM as a suppressor of M. tuberculosis–induced inflammation and virulence. In addition, cyclopropane stereochemistries on mycolic acids interact directly with host cells to both positively and negatively influence host innate immune activation.

Authors

Vivek Rao, Feng Gao, Bing Chen, William R. Jacobs, Michael S. Glickman

×

Figure 1

Loss of cmaA2 does not affect bacterial number but alters granuloma composition.

Options: View larger image (or click on image) Download as PowerPoint

                  Loss of cmaA2
                  does not affect bacte...
(A) WT C57BL/6J mice were infected by aerosol with WT M. tuberculosis (white bars) or the ΔcmaA2 mutant (black bars), and bacterial titers in lungs and spleen were determined at the indicated time points by serial dilution and plating of tissue homogenates. Each bar shows the mean value of bacterial loads from 3 mice per group with error bars indicating SEM. (B) Bacterial loads in lungs of animals infected intravenously with WT M. tuberculosis (white bars) or the ΔcmaA2 mutant (black bars). (C) Altered granuloma structure in tissues upon infection with ΔcmaA2. Representative liver granulomas (3 per infecting strain) from mice infected with WT, ΔcmaA2, and complemented (comp) strain. Magnification, ×400. See Results for statistical analysis of granuloma size and cellular composition. (D) H&E-stained lungs from C57BL/6J mice infected with the indicated strains and sacrificed 6 months after infection. See Results for quantitation of granulomatous inflammatory lesions.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts