Differential Monocyte Activation Underlies Strain-Specific<i>Mycobacterium tuberculosis</i>Pathogenesis

Manca, Claudia; Reed, Michael B.; Freeman, Sherry; Mathema, Barun; Kreiswirth, Barry N.; Barry, Clifton E.; Kaplan, Gilla

doi:10.1128/iai.72.9.5511-5514.2004

Cited by 206 publications

(193 citation statements)

References 22 publications

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“…Too little IL-12p70 was produced for detection in these assays. As reported previously (13,31), HN878 infection was associated with the release of smaller amounts of TNF-␣ and IL-10 than infection with H37Rv (Fig. 8A).…”

Section: G526a Mutation In the Unusual Profiles Of Dim And Pgl Producsupporting

confidence: 87%

“…These results support the concept that there is some flexibility in the structure of DIM that does not prevent these molecules to achieve their structural function in the cell envelope. The most striking phenotypes associated with the Beijing strains include their greater capacity to multiply within mice (11,34) and the weaker Th1-type immune response induced by these strains than by non-Beijing isolates (10,31). We therefore evaluated the impact of the Rv2952 G526A mutation on these phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Lane 1, extract from E. coli carrying the control vector; lane 2, extract from E. coli expressing the wild-type allele of Rv2952; lane 3, extract from E. coli expressing the Rv2952 G526A allele. induction of a weaker inflammatory response upon the infection of mouse BMDM than induced by the laboratory strain H37Rv (13,31). To test the possible relationship between this observation and the specific lipid profile of the Beijing strains, we compared the cytokine production by BMDM infected with wild-type or recombinant (HN878 and 94-1707) strains (Fig.…”

Section: G526a Mutation In the Unusual Profiles Of Dim And Pgl Producmentioning

confidence: 99%

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A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

Huet

Constant

Malaga

et al. 2009

Journal of Biological Chemistry

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The Mycobacterium tuberculosis Beijing strains are a family highly prevalent in Asia and have recently spread worldwide, causing a number of epidemics, suggesting that they express virulence factors not found in other M. tuberculosis strains. Accordingly, we looked for putative characteristic compounds by comparing the lipid profiles of several Beijing and non-Beijing strains. All the Beijing strains analyzed were found to synthesize structural variants of two well known characteristic lipids of the tubercle bacillus, namely phthiocerol dimycocerosates (DIM) and eventually phenolglycolipids (PGL). These variants were not found in non-Beijing M. tuberculosis isolates. Structural elucidation of these variants showed that they consist of phthiotriol and glycosylated phenolphthiotriol dimycocerosates, eventually acylated with 1 mol of palmitic acid, in addition to the conventional acylation of the ␤-diol by mycocerosic acids. We demonstrated that this unusual lipid profile resulted from a single point mutation in the Rv2952 gene, which encodes the S-adenosylmethionine-dependent methyltransferase participating to the O-methylation of the third hydroxyl of the phthiotriol and phenolphthiotriol in the biosynthetic pathway of DIM and PGL. Consistently, the mutated enzyme exhibited in vitro a much lower O-methyltransferase activity than did the wild-type Rv2952. We finally demonstrated that the structural variants of DIM and PGL fulfill the same function in the cell envelope and virulence than their conventional counterparts.

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Section: G526a Mutation In the Unusual Profiles Of Dim And Pgl Producsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: G526a Mutation In the Unusual Profiles Of Dim And Pgl Producmentioning

confidence: 99%

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A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

Huet

Constant

Malaga

et al. 2009

Journal of Biological Chemistry

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“…The recent discovery that the virulent Beijing strains cause human monocytes to express IL-4 and IL-13 is compatible with this [20]. However this simple concept has other implications, and can resolve several 6 outstanding paradoxes.…”

Section: The Importance Of the Mixed Th1/il4 Response To M Tuberculosismentioning

confidence: 81%

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

Rook

Dheda

Zumla

2005

Vaccine

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Tuberculosis vaccine candidates are entering clinical studies in areas where BCG fails. This is a high risk strategy. We suggest that geographical variation in the efficacy of BCG is related to the presence in developing countries of a cross-reactive background Th2-like response, probably attributable to exposure of mother and infant to helminths and environmental mycobacteria. Such Th2-like activity can stop M. tuberculosis from being pushed into a latent state by the Th1 response, impair bactericidal functions and cause toxicity of TNF-α and pulmonary fibrosis. A successful vaccine, rather than driving a Th1 response, might need to suppress this pre-existing subversive Th2-like component.

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“…28 These virulent strains have been shown to preferentially stimulate Th2 response more than other non-virulent strains. 29 From the ordered subset analysis of earlier onset of tuberculosis, the maximum linkage statistics (LOD ¼ 3.33) on chromosome 20p were derived from 30 of the 93 families, and the average minimum age at onset of tuberculosis in these families was 19.17 years. The 20p region is of particular interest for tuberculosis susceptibility because it has been shown to have significant evidence of linkage with leprosy.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

et al. 2008

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Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics ¼ 3.01, logarithm of odds (LOD) score ¼ 2.29, empirical P-value ¼ 0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score ¼ 2.57 and 3.33, permutation P-value ¼ 0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.

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Differential Monocyte Activation Underlies Strain-SpecificMycobacterium tuberculosisPathogenesis

Cited by 206 publications

References 22 publications

A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

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