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 A4 hydrolase, which catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB4 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 LTB4 production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
Figure 6C has a mortality curves for patiens from meningeal TB:
Interestingly, heterozygote advantage against tuberculosis has been offered as the reason for the high frequency of the cystic fibrosis allele in Europeans. TB has been around for at least 10,000 years.
ScienceDaily covers this paper, and a few other TB related ones, in the most recent issue of Cell.
Citation: Tobin et al. The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans. Cell, 2010; 140 (5): 717-730 DOI: 10.1016/j.cell.2010.02.013