Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.
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.
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
David M
DM
Tobin
Francisco J
FJ
Roca
Sungwhan F
SF
Oh
Ross
R
McFarland
Thad W
TW
Vickery
John P
JP
Ray
Dennis C
DC
Ko
Yuxia
Y
Zou
Nguyen D
ND
Bang
Tran T H
TT
Chau
Jay C
JC
Vary
Thomas R
TR
Hawn
Sarah J
SJ
Dunstan
Jeremy J
JJ
Farrar
Guy E
GE
Thwaites
Mary-Claire
MC
King
Charles N
CN
Serhan
Lalita
L
Ramakrishnan
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology; D017572:Leukotriene A4 / Q000235:genetics / Q000276:immunology; D007975:Leukotriene B4 / Q000235:genetics / Q000276:immunology; D044045:Lipoxins / Q000276:immunology; D008928:Mitochondria / Q000378:metabolism; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D019910:Mycobacterium marinum; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000276:immunology
D017572:Leukotriene A4; D044045:Lipoxins; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4