A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

Abstract

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.

Differential Influence of Nutrient-Starved Mycobacterium tuberculosis on Adaptive Immunity Results in Progressive Tuberculosis Disease and Pathology

“…Interestingly, in an attempt to discover the reason for the increased virulence of Beijing stains compared to other M. tuberculosis strains, it was found that all the analyzed Beijing strains synthesized structural variants of two well-known characteristic lipids of the tubercle bacillus, namely, phthiocerol dimycocerosates (DIM) and phenolglycolipids (PGL) (46), which correlated with higher CFU values (47,48). It could be speculated that the cell wall of StarvM.tb has a specific immune-activating lipid composition.…”

Correlates between Models of Virulence for Mycobacterium tuberculosis among Isolates of the Central Asian Lineage: a Case for Lysozyme Resistance Testing?

“…In this study, our approach was to identify naturally successful strains of M. tuberculosis from the population of London, United Kingdom, and to use the knowledge from previous in vivo and ex vivo studies carried out with isogenic strains (39)(40)(41) to develop hypotheses on and confirm/discover VFs relevant to their biology. We focused on closely related isolates from the CAS spoligotype family to minimize the potential impact that genetic background variability has on VF-associated phenotypes (25,43). Based on 15-locus MIRU-VNTR typing, each isolate of interest was associ- The genes corresponding to SNPs of interest (i.e., unique to C72 but not seen in C6, C14, or C40) were investigated in the literature.…”

“…2). We restricted our in silico analysis to all four CAS isolates (C6, C14, C72, and C40) to eliminate LSPs, RDs, and SNPs that define lineages and to reduce the impact that the genetic background might have on VF-associated (25,38,43) phenotypes. We first searched for the presence/absence of RD149 (Rv1573-Rv1584c), as its absence was previously associated with reduced intracellular growth of CAS strains in THP-1 cells (56).…”

“…It has become clear, however, that the previously unrecognized genetic diversity among M. tuberculosis isolates has an impact on the outcome of infection (17-19), and different approaches have been undertaken towards a better understanding of what makes a strain virulent. Some studies have attempted to tie epidemiological data to mechanistic explanations; for example, emerging Beijing strains are believed to be more virulent or associated with increased progression to disease (18,(20)(21)(22), and their glycolipids are believed to contribute to their phenotype (23)(24)(25)(26). Outbreak strains were also found to have remarkable growth properties in animal models (27,28) or to induce a differential protective host response (29-31).…”

“…In the present study, we set out to identify new VFs (42) by using clinically relevant M. tuberculosis isolates instead of the laboratory-adapted reference strain H37Rv. Since VFs are likely to be lineage specific (25,38,43), we focused on three strains from an identical lineage that were isolated in a population-based study of TB in London over a period of 1 year; each isolate of interest was selected from one of the three commonest clusters of that year, according to 15-locus mycobacterial interspersed repetitive-unitvariable-number tandem-repeat (MIRU-VNTR) typing (37). We hypothesized that these strains might perform differently in various models commonly used for the study of M. tuberculosis virulence as a result of slight variations in their genomes (some of which potentially encode VFs) and as suggested by their associated and differential human cluster sizes.…”