Sequestration of host metabolism by an intracellular pathogen.
Sequestration of host metabolism by an intracellular pathogen.
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通过细胞内病原体隔离宿主代谢。
DOI：
10.7554/elife.12552
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发表时间：
2016-03-16
期刊：
影响因子：
7.7
通讯作者：
Subtil A
中科院分区：
文献类型：
--
作者：
Gehre L;Gorgette O;Perrinet S;Prevost MC;Ducatez M;Giebel AM;Nelson DE;Ball SG;Subtil A
对于细胞内的病原体来说，停留在液泡中提供了一种抵御细胞质宿主防御的场所，但代价是获得有限的营养。人类病原体沙眼衣原体生长在富含糖原的空泡中。这种大的聚合物是如何在那里积累的还是个未知数。我们揭示了宿主糖原储存通过两条途径转移到液泡：从细胞质池大量吸收和从头合成。我们提供了细菌糖原代谢酶通过3型分泌物分泌到液泡腔的证据。我们的数据为以下情况提供了强有力的支持：细菌通过细菌糖原合成酶的显著适应，选择宿主转运蛋白SLC35D2将UDP-葡萄糖输入到液泡中，作为从头合成糖原的底物。基于这些发现，我们认为，寄生性液泡不仅提供保护，而且还提供一个微生物控制的代谢活性隔室，对于将宿主资源重新定向到病原体是必不可少的。DOI：http://dx.doi.org/10.7554/eLife.12552.001沙眼衣原体是最常见的致病的性传播细菌。感染通常不会产生任何明显的症状，但如果不治疗，可能会导致不孕或其他严重问题。这种微生物也是感染剂致盲的主要原因。细菌通过感染宿主细胞在人体内生长。在这些细胞内，细菌被发现在被称为内涵体的隔间内，内涵体保护它们免受宿主的防御反应，并使它们能够为自己创造一个舒适的环境。然而，这是有代价的，因为细菌无法立即获得宿主细胞其余部分的营养。因此，沙眼衣原体已经找到了将这些营养物质输入到包涵体中的方法，更广泛地说，控制了它与宿主细胞的相互作用。沙眼衣原体形成的包涵体含有大量的糖原，这是一种碳水化合物，通常作为能量储存分子。虽然这一观察是在几十年前进行的，但如此大的分子积累在包裹体中的分子机制尚不清楚。Gehre等人。现在已经使用了各种细胞生物学技术来解决这个问题。实验表明，糖原在包裹体中有两种不同的积累途径。一些糖原从宿主细胞内部大量运输到包涵体中。然而，细菌也会从一种名为UDP-葡萄糖的积木分子中产生新的糖原。为了做到这一点，细菌招募了一个宿主运输分子到包涵体周围的膜上。这种运输分子将UDP-葡萄糖带入包涵体，细菌释放的一种名为糖原合成酶的酶使用UDP-葡萄糖制造糖原。沙眼衣原体糖原合成酶是不寻常的，因为大多数其他细菌只能从另一种类型的葡萄糖中制造糖原。通过使用这两种途径，沙眼衣原体能够将感染细胞的大部分糖原储存在包涵体内，使宿主无法接触到它们，但准备好供细菌使用。以前的研究表明，沙眼衣原体比其他衣原体细菌在积累糖原方面要好得多。因此，未来的挑战将是找出这到底是如何帮助沙眼衣原体在人类细胞内生存的。DOI：http://dx.doi.org/10.7554/eLife.12552.002
For intracellular pathogens, residence in a vacuole provides a shelter against cytosolic host defense to the cost of limited access to nutrients. The human pathogen Chlamydia trachomatis grows in a glycogen-rich vacuole. How this large polymer accumulates there is unknown. We reveal that host glycogen stores shift to the vacuole through two pathways: bulk uptake from the cytoplasmic pool, and de novo synthesis. We provide evidence that bacterial glycogen metabolism enzymes are secreted into the vacuole lumen through type 3 secretion. Our data bring strong support to the following scenario: bacteria co-opt the host transporter SLC35D2 to import UDP-glucose into the vacuole, where it serves as substrate for de novo glycogen synthesis, through a remarkable adaptation of the bacterial glycogen synthase. Based on these findings we propose that parasitophorous vacuoles not only offer protection but also provide a microorganism-controlled metabolically active compartment essential for redirecting host resources to the pathogens. DOI: http://dx.doi.org/10.7554/eLife.12552.001 Chlamydia trachomatis is the most common sexually transmitted bacteria that causes disease. Infections often do not produce any obvious symptoms, but can lead to infertility or other severe problems if left untreated. This microbe is also the leading cause of blindness by an infectious agent.The bacteria grow in the human body by infecting host cells. Inside these cells, the bacteria are found inside compartments known as inclusions, which protect them from the host’s defense responses and enable them to create a comfortable environment for themselves. However, this comes at a cost because the bacteria lose immediate access to the nutrients in the rest of the host cell. Thus, C.trachomatis has developed ways to import these nutrients into inclusions, and, more generally, to take the control of its interactions with the host cell. The inclusions built up by C. trachomatis contain a high amount of glycogen, a carbohydrate that generally acts as an energy storage molecule. Although this observation was made many decades ago, the molecular mechanism by which such a large molecule accumulates in the inclusion has not been clarified. Gehre et al. have now used a variety of cell biology techniques to address this question. The experiments show that there are two different pathways through which glycogen accumulates within the inclusion. Some glycogen is transported in bulk from the interior of the host cell into the inclusion. However, the bacteria also make new glycogen in the inclusion from a building block molecule called UDP-glucose. To do this, the bacteria recruit a host transport molecule to the membrane that surrounds the inclusion. This transport molecule brings UDP-glucose into the inclusion, where an enzyme called glycogen synthase – which is released by the bacteria – uses the UDP-glucose to make glycogen. The C. trachomatis glycogen synthase is unusual because most other bacteria can only make glycogen from another type of glucose. By using both pathways, C. trachomatis is able to trap most of the glycogen stores of the infected cell within the inclusion so that they are inaccessible to the host but ready for the bacteria to use. Previous work has shown that C. trachomatis is much better at accumulating glycogen than other Chlamydia bacteria are. Therefore, a future challenge will be to find out exactly how this helps C. trachomatis survive inside human cells. DOI: http://dx.doi.org/10.7554/eLife.12552.002