Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cell. 2012 Feb 3;148(3):434-46. doi: 10.1016/j.cell.2011.12.023.

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

Author information

  • 1Department of Microbiology, University of Washington, Seattle, WA 98195, USA.

Abstract

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
22304914
[PubMed - indexed for MEDLINE]
PMCID:
PMC3433720
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk