ZFIN ID: ZDB-PUB-120207-9
Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections
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.
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 (all 25) expand
PubMed: 22304914 Full text @ Cell
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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 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.

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