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

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dc.contributor.authorOh, Sungwhan F.
dc.contributor.authorMcFarland, Ross
dc.contributor.authorVickery, Thad W.
dc.contributor.authorRay, John P.
dc.contributor.authorKo, Dennis C.
dc.contributor.authorZou, Yuxia
dc.contributor.authorBang, Nguyen D.
dc.contributor.authorChau, Tran T. H.
dc.contributor.authorVary, Jay C.
dc.contributor.authorHawn, Thomas R.
dc.contributor.authorDunstan, Sarah J.
dc.contributor.authorFarrar, Jeremy J.
dc.contributor.authorThwaites, Guy E.
dc.contributor.author King, Mary-Claire
dc.contributor.authorSerhan, Charles N.
dc.contributor.authorRamakrishnan, Lalita
dc.contributor.authorTobin, David M.
dc.contributor.authorRoca Soler, Francisco José
dc.contributor.departmentBioquímica y Biología Molecular B e Inmunología
dc.date.accessioned2026-02-25T16:45:24Z
dc.date.available2026-02-25T16:45:24Z
dc.date.copyright© 2012 Elsevier Inc.
dc.date.issued2012-02-03
dc.description.abstractSusceptibility 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.
dc.formatapplication/pdf
dc.format.extent13
dc.identifier.citationCell, Volume 148, Issue 3, 3 february 2012, Pages 434-446
dc.identifier.doihttps://doi.org/10.1016/j.cell.2011.12.023
dc.identifier.eissn1097-4172
dc.identifier.issn0092-8674
dc.identifier.urihttp://hdl.handle.net/10201/213681
dc.languageeng
dc.publisherCell Press
dc.relationFunded by grants from the NIH (L.R., C.N.S.), an American Cancer Society postdoctoral fellowship and a Mallinckrodt Scholar Award (D.M.T.), a postdoctoral fellowship from the educational ministry of Spain (F.J.R.), the NWRCE for Biodefense and Emerging Infectious Diseases Research (L.R. and D.C.K.), the Burroughs Wellcome Fund (L.R. and T.R.H.), the Wellcome Trust, UK (G.T., J.F., S.D., T.T.H.C. and N.D.B.), the American Skin Association, the Dermatology Foundation, and an NIH postdoctoral fellowship grant (J.C.V.), and the Chinese Academy of Sciences (Y.Z.). M.C.K. is an American Cancer Society Professor. D.M.T. is a recipient of the NIH Director’s New Innovator Award and L.R. is a recipient of the NIH Director’s Pioneer Award
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0092867412000104?via%3Dihub
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subject.odsObjetivo 3: Salud
dc.titleHost genotype-specific therapies can optimize the inflammatory response to mycobacterial infections
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
relation.isAuthorOfPublication7f46a88a-1ff4-4f80-948e-7d636b80e75d
relation.isAuthorOfPublication.latestForDiscovery7f46a88a-1ff4-4f80-948e-7d636b80e75d
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