Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections
- Authors
- Tobin, D.M., Roca, F.J., Oh, S.F., McFarland, R., Vickery, T.W., Ray, J.P., Ko, D.C., Zou, Y., Bang, N.D., Chau, T.T., Vary, J.C., Hawn, T.R., Dunstan, S.J., Farrar, J.J., Thwaites, G.E., King, M.C., Serhan, C.N., and Ramakrishnan, L.
- ID
- ZDB-PUB-120207-9
- Date
- 2012
- Source
- Cell 148(3): 434-446 (Journal)
- Registered Authors
- McFarland, Ross, Ramakrishnan, Lalita, Roca, Francisco Jose, Tobin, David, Zou, Yuxia
- Keywords
- none
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Humans
- Inflammation/immunology
- Leukotriene A4/genetics
- Leukotriene A4/immunology
- Leukotriene B4/genetics
- Leukotriene B4/immunology
- Lipoxins/immunology
- Mitochondria/metabolism
- Mycobacterium Infections/drug therapy*
- Mycobacterium Infections/genetics
- Mycobacterium Infections/immunology*
- Mycobacterium marinum
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Signal Transduction
- Transcription, Genetic
- Tuberculosis, Meningeal/drug therapy*
- Tuberculosis, Meningeal/genetics
- Tuberculosis, Meningeal/immunology*
- Tumor Necrosis Factor-alpha/metabolism
- Zebrafish/embryology
- Zebrafish/immunology
- PubMed
- 22304914 Full text @ Cell
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 A4 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 B4. 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.