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Tobin D.M.,University of Washington | Vary Jr. J.C.,University of Washington | Ray J.P.,University of Washington | Walsh G.S.,Fred Hutchinson Cancer Research Center | And 8 more authors.
Cell | Year: 2010

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. © 2010 Elsevier Inc. All rights reserved. Source


Krishnan N.,Imperial College London | Malaga W.,CNRS Institute of Pharmacology and Structural Biology | Malaga W.,Toulouse 1 University Capitole | Constant P.,CNRS Institute of Pharmacology and Structural Biology | And 14 more authors.
PLoS ONE | Year: 2011

The six major genetic lineages of Mycobacterium tuberculosis are strongly associated with specific geographical regions, but their relevance to bacterial virulence and the clinical consequences of infection are unclear. Previously, we found that in Vietnam, East Asian/Beijing and Indo-Oceanic strains were significantly more likely to cause disseminated tuberculosis with meningitis than those from the Euro-American lineage. To investigate this observation we characterised 7 East Asian/Beijing, 5 Indo-Oceanic and 6 Euro-American Vietnamese strains in bone-marrow-derived macrophages, dendritic cells and mice. East Asian/Beijing and Indo-Oceanic strains induced significantly more TNF-α and IL-1β from macrophages than the Euro-American strains, and East Asian/Beijing strains were detectable earlier in the blood of infected mice and grew faster in the lungs. We hypothesised that these differences were induced by lineage-specific variation in cell envelope lipids. Whole lipid extracts from East Asian/Beijing and Indo-Oceanic strains induced higher concentrations of TNF-α from macrophages than Euro-American lipids. The lipid extracts were fractionated and compared by thin layer chromatography to reveal a distinct pattern of lineage-associated profiles. A phthiotriol dimycocerosate was exclusively produced by East Asian/Beijing strains, but not the phenolic glycolipid previously associated with the hyper-virulent phenotype of some isolates of this lineage. All Indo-Oceanic strains produced a unique unidentified lipid, shown to be a phenolphthiocerol dimycocerosate dependent upon an intact pks15/1 for its production. This was described by Goren as the 'attenuation indictor lipid' more than 40 years ago, due to its association with less virulent strains from southern India. Mutation of pks15/1 in a representative Indo-Oceanic strain prevented phenolphthiocerol dimycocerosate synthesis, but did not alter macrophage cytokine induction. Our findings suggest that the early interactions between M. tuberculosis and host are determined by the lineage of the infecting strain; but we were unable to show these differences are driven by lineage-specific cell-surface expressed lipids. © 2011 Krishnan et al. Source


Oramasionwu G.E.,Centers for Disease Control and Prevention | Heilig C.M.,Centers for Disease Control and Prevention | Udomsantisuk N.,Chulalongkorn University | Kimerling M.E.,Bill and Melinda Gates Foundation | And 5 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2013

BACKGROUND: Delayed diagnosis of tuberculosis (TB) increases mortality. OBJECTIVE: To evaluate whether stool culture improves the diagnosis of TB in people living with the human immuno deficiency virus (PLHIV). DESIGN: We analysed cross-sectional data of TB diagnosis in PLHIV in Cambodia, Thailand and Viet Nam. Logistic regression was used to assess the association between positive stool culture and TB, and to calculate the incremental yield of stool culture. RESULTS: A total of 1693 PLHIV were enrolled with a stool culture result. Of 228 PLHIV with culturec onfirmed TB from any site, 101 (44%) had a positive stool culture; of these, 91 (90%) had pulmonary TB (PTB). After adjusting for confounding factors, a positive stool culture was associated with smear-negative (odds ratio [OR] 26, 95% confidence interval [CI] 12-58), moderately smear-positive (OR 60, 95%CI 23-159) and highly smear-positive (OR 179, 95%CI 59-546) PTB compared with no PTB. No statistically significant association existed with extra-pulmonary TB compared with no extra-pulmonary TB (OR 2, 95%CI 1-5). The incremental yield of one stool culture above two sputum cultures (5%, 95%CI 3-8) was comparable to an additional sputum culture (7%, 95%CI 4-11). CONCLUSION: Nearly half of the PLHIV with TB had a positive stool culture that was strongly associated with PTB. Stool cultures may be used to diagnose TB in PLHIV. © 2013 The Union. Source


Graustein A.D.,University of Washington | Horne D.J.,University of Washington | Arentz M.,University of Washington | Bang N.D.,Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease | And 7 more authors.
Tuberculosis | Year: 2015

Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p < 0.05) while three additional SNPs neared significance (0.05 < p < 0.1). When these six SNPs were evaluated in a validation cohort (n = 339 cases, 367 controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p = 0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p = 0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis. © 2015 Elsevier Ltd. All rights reserved. Source


Thuong N.T.T.,Cornell University | Hawn T.R.,University of Washington | Chau T.T.H.,Hospital for Tropical Diseases | Bang N.D.,Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease | And 9 more authors.
Genes and Immunity | Year: 2012

Although host genetics influences susceptibility to Mycobacterium tuberculosis, the human genes regulating pathogenesis remain largely unknown. We used M. tuberculosis-stimulated macrophage gene expression profiling in conjunction with a case-control genetic association study to discover epiregulin (EREG), as a novel candidate tuberculosis (TB) susceptibility gene. Using a genome-wide association study dataset, we found that among the 21 genes with greater than 50-fold induction, EREG had the most polymorphisms associated with TB. We genotyped haplotype-tagging polymorphisms in discovery (N=337 cases, N=380 controls) and validation (N=332 cases) datasets and an EREG polymorphism (rs7675690) was associated with susceptibility to TB (genotypic comparison; corrected P=0.00007). rs7675690 was also associated more strongly with infections caused by the Beijing lineage of M. tuberculosis when compared with non-Beijing strains (controls vs Beijing, OR 7.81, P=8.7 × 10 -5; non-Beijing, OR 3.13, P=0.074). Furthermore, EREG expression was induced in monocytes and peripheral blood mononuclear cells stimulated with M. tuberculosis as well as TLR4 and TLR2/1/6 ligands. In murine macrophages, EREG expression induced by M. tuberculosis was MYD88- and TLR2-dependent. Together, these data provide the first evidence for an important role for EREG as a susceptibility gene for human TB. © 2012 Macmillan Publishers Limited All rights reserved. Source

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