Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule Journal Article
| Authors: | Rao, V.; Fujiwara, N.; Porcelli, S. A.; Glickman, M. S. |
| Article Title: | Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule |
| 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. |
| Keywords: | controlled study; unclassified drug; mutation; pathogenesis; nonhuman; protein function; animal cell; mouse; animals; mice; mice, knockout; cell line; animal model; mice, inbred c57bl; mycobacterium tuberculosis; cyclopropanes; methyltransferases; immune response; tumor necrosis factor-alpha; interleukin 6; interleukin-6; chemical structure; macrophages; bacterial infection; tumor necrosis factor; chemical modification; enzyme; bacterial growth; granulomatous inflammation; macrophage activation; bacterial membrane; immunity, natural; colony count, microbial; cord factor; cyclopropane; cord factors; cyclopropane synthase; tuberculosis, pulmonary |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 201 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2005-02-21 |
| Start Page: | 535 |
| End Page: | 543 |
| Language: | English |
| DOI: | 10.1084/jem.20041668 |
| PUBMED: | 15710652 |
| PROVIDER: | scopus |
| PMCID: | PMC2213067 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 90" - "Export Date: 24 October 2012" - "CODEN: JEMEA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work