Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections

• Published in: Cell Vol. 148; no. 3; pp. 434 - 446
• Main Authors: Tobin, David M., Roca, Francisco J., Oh, Sungwhan F., McFarland, Ross, Vickery, Thad W., Ray, John P., Ko, Dennis C., Zou, Yuxia, Bang, Nguyen D., Chau, Tran T.H., Vary, Jay C., Hawn, Thomas R., Dunstan, Sarah J., Farrar, Jeremy J., Thwaites, Guy E., King, Mary-Claire, Serhan, Charles N., Ramakrishnan, Lalita
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2012
• Subjects: Animals; Danio rerio; Disease Models, Animal; eicosanoids; genotype; Humans; immune response; inflammation; Inflammation - immunology; Leukotriene A4 - genetics; Leukotriene A4 - immunology; Leukotriene B4 - genetics; Leukotriene B4 - immunology; Lipoxins - immunology; loci; meningitis; Mitochondria - metabolism; Mycobacterium; Mycobacterium Infections - drug therapy; Mycobacterium Infections - genetics; Mycobacterium Infections - immunology; Mycobacterium marinum; patients; polymorphism; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Signal Transduction; single nucleotide polymorphism; therapeutics; transcription (genetics); Transcription, Genetic; tuberculosis; Tuberculosis, Meningeal - drug therapy; Tuberculosis, Meningeal - genetics; Tuberculosis, Meningeal - immunology; Tumor Necrosis Factor-alpha - metabolism; tumor necrosis factors; Zebrafish - embryology; Zebrafish - immunology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.12.023

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. [Display omitted] ► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.