Comparisons of mutants lacking the golgi UDP-Galactose or GDP-Mannose transporters establish that phosphoglycans are important for promastigote but not amastigote virulence in Leishmania major
Comparisons of mutants lacking the golgi UDP-Galactose or GDP-Mannose transporters establish that phosphoglycans are important for promastigote but not amastigote virulence in Leishmania major
复制标题
DOI：
10.1128/iai.00735-07
复制
发表时间：
2007-09-01
影响因子：
3.1
通讯作者：
Beverley, Stephen M.
中科院分区：
文献类型：
--
作者：
Capul, Althea A.;Hickerson, Suzanne;Beverley, Stephen M.
含有[Gal（0 1，4）Man（α 1P04）]衍生的重复单元的丰富的表面利什曼原虫磷酸糖聚糖（PG）在这种原生动物寄生虫的感染循环中的几个点是重要的。PG合成需要将活化的核苷酸-糖前体从细胞质运输到高尔基体。相应地，L.主要的GDP-甘露糖转运蛋白LPG2缺乏PG，并且在易感小鼠中巨噬细胞存活和急性病理学诱导方面严重受损，然而它们能够无限期地持续并诱导保护性免疫。而lpg 2（-）L.墨西哥无鞭毛体类似地缺乏PG，但在其他方面在已知的糖缀合物中正常，仍然能够诱导急性病理学。为了进一步探索这一点，我们测试了新的PG-nu11 L的感染性。主要突变体，其在两个UDP-半乳糖转运蛋白基因LPG5A和LPG5B中失活。令人惊讶的是，该突变体并没有重现L. major lpg2（-），而不是类似于L.主要脂磷酸聚糖缺陷型Ipgl突变体。代谢环lpg5A-Ilpg5B-前鞭毛体在巨噬细胞感染和存活的初始步骤中显示出强烈的缺陷。然而，在适度的延迟后，1pg5A-11pg5B-突变体在感染小鼠中诱导病变病理，此后正常进展。从这些病变中恢复的无鞭毛体在小鼠和巨噬细胞中完全感染，尽管继续缺乏PG。这表明另一种LPG2（-）依赖性代谢产物是导致L。主要无鞭毛体毒力缺陷，虽然进一步的研究排除了细胞质marmans。因此，这些数据解决了不同的表型Ipg 2-利什曼原虫物种中看到的强调的作用，糖缀合物以外的PG在无鞭毛体毒力，同时提供进一步的支持PG的作用，在后环前鞭毛体毒力。
Abundant surface Leishmania phosphogiycans (PGs) containing [Gal (0 1,4) Man (alpha 1P04)-derived repeating units are important at several points in the infectious cycle of this protozoan parasite. PG synthesis requires transport of activated nucleotide-sugar precursors from the cytoplasm to the Golgi apparatus. Correspondingly, null mutants of the L. major GDP-mannose transporter LPG2 lack PGs and are severely compromised in macrophage survival and induction of acute pathology in susceptible mice, yet they are able to persist indefinitely and induce protective immunity. However, lpg2(-) L. mexicana amastigotes similarly lacking PGs but otherwise normal in known glycoconjugates remain able to induce acute pathology. To explore this further, we tested the infectivity of a new PG-nu11 L. major mutant, which is inactivated in the two UDP-galactose transporter genes LPG5A and LPG5B. Surprisingly this mutant did not recapitulate the phenotype of L. major lpg2(-), instead resembling the L. major lipophosphoglycan-deficient Ipgl- mutant. Metacyclic lpg5A-Ilpg5B- promastigotes showed strong defects in the initial steps of macrophage infection and survival. However, after a modest delay, the 1pg5A-11pg5B- mutant induced lesion pathology in infected mice,, vhich thereafter progressed normally. Amastigotes recovered from these lesions were fully infective in mice and in macrophages despite the continued absence of PGs. This suggests that another LPG2(-)dependent metabolite is responsible for the L. major amastigote virulence defect, although further studies ruled out cytoplasmic marmans. These data thus resolve the distinct phenotypes seen among Ipg2- Leishmania species by emphasizing the role of glycoconjugates other than PGs in amastigote virulence, while providing further support for the role of PGs in metacyclic promastigote virulence.