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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tobin, DM; Roca, FJ; Oh, SF; McFarland, R; Vickery, TW; Ray, JP; Ko, DC; Zou, Y; Bang, ND; Chau, TTH; Vary, JC; Hawn, TR; Dunstan, SJ; Farrar, JJ; Thwaites, GE; King, M-C; Serhan, CN; Ramakrishnan, L

Published Date

  • February 3, 2012

Published In

Volume / Issue

  • 148 / 3

Start / End Page

  • 434 - 446

PubMed ID

  • 22304914

Pubmed Central ID

  • PMC3433720

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2011.12.023


  • eng

Conference Location

  • United States