Summary 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.
SUMMARY 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.
The mechanisms used by Shiga toxin (Stx)-producing Escherichia coli to adhere to epithelial cells are incompletely understood. Two cosmids from an E. coli O157:H7 DNA library contain an adherence-conferring chromosomal gene encoding a protein similar to iron-regulated gene A (IrgA) of Vibrio cholerae (M. B. Goldberg, S. A. Boyko, J. R. Butterton, J. A. Stoebner, S. M. Payne, and S. B. Calderwood, Mol. Microbiol. 6:2407-2418, 1992). We have termed the product of this gene the IrgA homologue adhesin (Iha), which is encoded by iha. Iha is 67 kDa in E. coli O157:H7 and 78 kDa in laboratory E. coli and is structurally unlike other known adhesins. DNA adjacent to iha contains tellurite resistance loci and is conserved in structure in distantly related pathogenic E. coli, but it is absent from nontoxigenic E. coli O55:H7, sorbitol-fermenting Stx-producing E. coli O157:H؊, and laboratory E. coli. We have termed this region the tellurite resistance-and adherence-conferring island. We conclude that Iha is a novel bacterial adherence-conferring protein and is contained within an E. coli chromosomal island of conserved structure. Pathogenic E. coli O157:H7 has only recently acquired this island.Escherichia coli O157:H7 and other Shiga toxin (Stx)-producing E. coli (STEC) strains cause diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome. The mechanisms underlying the adherence of STEC to epithelial cells are only partly understood (35). The ability to adhere to epithelial cells is an important virulence trait, because adherence presumably enables enteric pathogens to deliver toxins efficiently to host organs, overcome peristaltic clearance, and gain access to hostderived nutrients.Intimin is the best-characterized E. coli O157:H7 adherence molecule. Encoded by eae, intimin mediates the attaching and effacing lesion caused by enteropathogenic E. coli (EPEC) and many STEC serotypes (21) and is an important component of pathogenicity. However, cloned eae from EPEC and STEC do not confer the adherent phenotype upon laboratory E. coli (18,25,28). Moreover, though the cloned EPEC locus of enterocyte effacement, which includes eae, does confer the adherence phenotype on E. coli K-12 (27), the cloned E. coli O157:H7 locus of enterocyte effacement does not (12).We describe an E. coli O157:H7 gene that renders laboratory E. coli adherent to epithelial cells and explore evolutionary aspects of its acquisition.(These data were presented in part at the 3rd International Symposium and Workshop on Shiga Toxin-Producing Escherichia coli Infections, Baltimore, Md., 22 to 26 June 1997.) MATERIALS AND METHODSBacteria. The bacteria analyzed in this study are described in Table 1. The bacteria were inoculated directly from frozen stock (in Luria-Bertani [LB] broth-15% glycerol, maintained at Ϫ70°C) into LB broth (26). The cultures were grown overnight under standardized conditions (37°C; 14 to 16 h; stationary cultures) for adherence assays and protein preparations. The bacteria were grown in a shaking incubator (37°C; 14 to 24 h) f...
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