肺結(jié)核在多數(shù)情況下用多藥物療法是可以治愈的,，但對相當(dāng)一部分患者,，這種療法沒有療效。不同患者的不同療效通常被認(rèn)為是由于不同的人對一種在遺傳上比較穩(wěn)定的病原體的感染有不同的反應(yīng),。一項新的研究對這種觀點提出了挑戰(zhàn),。該研究結(jié)果表明，病原體也是可以發(fā)生變化的,。研究人員發(fā)現(xiàn),，分支桿菌肺結(jié)核“W-北京分離菌種”的一個亞類（據(jù)稱在小鼠中是超惡性的）能產(chǎn)生一種特定分子PGL，在試管實驗中它能抑制先天免疫響應(yīng),。到目前為止,，PGL與肺結(jié)核超惡性之間的聯(lián)系僅限于這一模型體系，但該結(jié)果提出這樣一個可能性：細(xì)菌因子的可變表達(dá)在人體中也許也能影響病情的發(fā)展,，也許能開發(fā)出針對特定菌種的治療方法,。
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.
