肺结核在多数情况下用多药物疗法是可以治愈的，但对相当一部分患者，这种疗法没有疗效。不同患者的不同疗效通常被认为是由于不同的人对一种在遗传上比较稳定的病原体的感染有不同的反应。一项新的研究对这种观点提出了挑战。该研究结果表明，病原体也是可以发生变化的。研究人员发现，分支杆菌肺结核“W-北京分离菌种”的一个亚类（据称在小鼠中是超恶性的）能产生一种特定分子PGL，在试管实验中它能抑制先天免疫响应。到目前为止，PGL与肺结核超恶性之间的联系仅限于这一模型体系，但该结果提出这样一个可能性：细菌因子的可变表达在人体中也许也能影响病情的发展，也许能开发出针对特定菌种的治疗方法。
A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response
Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2–3 million lives from tuberculosis worldwide1. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis2, 3, there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes4-7. Here we describe the identification and functional relevance of a highly biologically active lipid species—a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family8 that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor- and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner.
Figure 1 PGL is produced by HN878 and related W-Beijing strains. a, Lipids extracted from [14C]propionic-acid-labelled cultures of the strains indicated were analysed by TLC. The positions of the lipids specific to HN878 and 210 are highlighted (arrows). b, Lipids of [14C]propionic-acid-labelled HN878 (top panel) and pks1-15::hyg (bottom panel) were analysed by two-dimensional TLC, demonstrating loss of the HN878-specific lipids (arrow) in pks1-15::hyg. c, Model structures of PDIM and PGL. The region of PGL predicted to be derived from Pks1-15 (ref. 16) and the position of a variable number of carbohydrate residues (S) attached to the phenyl moiety are shown. d, TLC of lipids extracted from [14C]p-hydroxybenzoic-acid-labelled cultures including the complemented attB::pks1-15 strain.
Figure 2 PGL is responsible for the hypervirulent phenotype of HN878 in mice. a, Six-week-old B6D2 F1 mice were infected via aerosol with HN878 (solid line) and pks1-15::hyg (dotted line). At 3 h and 2, 5 and 12 weeks after infection lungs were homogenized and plated for c.f.u. determination (3–4 mice per group). Values are log10(c.f.u.) ( s.e.m.). At necropsy, lung c.f.u. were obtained for HN878 (black column) and pks1-15::hyg (grey column) (inset). b, At 2, 5 and 12 weeks after infection spleens were homogenized and plated. c, Survival analysis was carried out for additional mice (11 mice per group) infected with HN878 (filled circles), H37Rv (open squares), pks1-15::hyg (filled triangles) and CDC1551 (open diamonds).
Figure 3 PGL-mediated inhibition of pro-inflammatory cytokine release by murine BMMs. a, Culture supernatants obtained 24 h after BMM infections were analysed by ELISA for the presence of the cytokines TNF-, IL-6, IL-12 and the chemokine MCP-1. Data obtained from one representative experiment performed in triplicate are presented ( s.e.m.). b, BMMs were incubated for 24 h in the presence of increasing amounts of purified PGL (0, 1 or 10 µg) in addition to apolar lipids (5 µg) extracted from HN878 pks1-15::hyg and H37Rv. Culture supernatants were analysed by ELISA for TNF-, IL-6 and MCP-1. IL-12 was unable to be detected in these lipid assays. PGL alone showed no effect in these assays. Representative data ( s.e.m.) from a single experiment performed in triplicate are presented. c, BMMs were incubated for 24 h in the presence of 2 µg purified PGL, M. bovis (BCG) PGL or PDIM in addition to apolar lipids (1 µg) extracted from HN878 pks1-15::hyg. Culture supernatants were analysed in triplicate ( s.e.m.) by ELISA for TNF- and IL-6.
