The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.
Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
Tobin
David M
DM
Department of Microbiology, University of Washington, Box 357242, Seattle, WA 98195, USA.
Vary
Jay C
JC
Ray
John P
JP
Walsh
Gregory S
GS
Dunstan
Sarah J
SJ
Bang
Nguyen D
ND
Hagge
Deanna A
DA
Khadge
Saraswoti
S
King
Mary-Claire
MC
Hawn
Thomas R
TR
Moens
Cecilia B
CB
Ramakrishnan
Lalita
L
D000818:Animals; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics*; D005393:Fish Diseases / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007918:Leprosy / Q000235:genetics* / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology; D015027:Zebrafish
D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase