Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence Journal Article
| Authors: | Rao, V.; Gao, F.; Chen, B.; Jacobs, W. R. Jr; Glickman, M. S. |
| Article Title: | Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence |
| 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. |
| Keywords: | controlled study; survival rate; unclassified drug; pathogenesis; nonhuman; animal cell; mouse; phenotype; animals; mice; animal tissue; cells, cultured; infection; animal experiment; animal model; inflammation; mice, scid; bacterial virulence; mice, inbred balb c; mice, inbred c57bl; mycolic acid; mycobacterium tuberculosis; bacterial proteins; cyclopropanes; methyltransferases; mycolic acids; tumor necrosis factor alpha; tumor necrosis factor-alpha; gamma interferon; lung; innate immunity; immunomodulation; macrophage; macrophages; host cell; tuberculosis; stereochemistry; granuloma; enzyme; cyclopropanation; membrane lipids; interferon type ii; cord factor; cyclopropane; mycolic acid synthase; petroleum ether; cord factors |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 116 |
| Issue: | 6 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2006-06-01 |
| Start Page: | 1660 |
| End Page: | 1667 |
| Language: | English |
| DOI: | 10.1172/jci27335 |
| PUBMED: | 16741578 |
| PROVIDER: | scopus |
| PMCID: | PMC1464906 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 63" - "Export Date: 4 June 2012" - "CODEN: JCINA" - "Source: Scopus" |
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