來自美國加州大學(xué)舊金山分校的一個研究小組利用來自細(xì)菌的天然蛋白在免疫細(xì)胞中構(gòu)建一種“暫停開關(guān)(pause switch)”，從而潛在地導(dǎo)致人們開發(fā)出更加有效和安全的免疫療法來治療諸如癌癥和多發(fā)性硬化癥之類的疾病,。
這些“效應(yīng)蛋白”是由一些細(xì)菌產(chǎn)生的,，它們能夠保護自己免受宿主免疫系統(tǒng)的攻擊：它們侵襲宿主免疫細(xì)胞，關(guān)閉免疫反應(yīng)足夠長的時間以便允許細(xì)菌進行復(fù)制,。
在這些于2012年7月22日在線發(fā)表在《自然》期刊上的新發(fā)現(xiàn)中,，研究小組證實他們能夠?qū)⑦@些效應(yīng)蛋白從細(xì)菌中移走，并將它們導(dǎo)入酵母或人免疫T細(xì)胞從而在經(jīng)過基因改造的細(xì)胞中構(gòu)建一種“暫停開關(guān)”,。最終,，他們希望利用這種暫停開關(guān)開發(fā)出免疫療法從而使得他們更加容易控制這些療法，以便使得副作用最小化,。
在此之前,，已有大量實驗利用免疫系統(tǒng)對抗癌癥和自身免疫疾病,，而且科學(xué)家們能夠重新訓(xùn)練免疫系統(tǒng)來攻擊患病細(xì)胞，但是如何以一種可控制的方式實施,，還是一個問題,。通常，當(dāng)研究人員對T細(xì)胞進行基因改造以便用于治療疾病,，阻止這些細(xì)胞過度活躍的唯一方法就是插入編碼一種“自我摧毀”開關(guān)的DNA,，然后利用這種開關(guān)殺死細(xì)胞。而在這項新的研究中,，研究人員開發(fā)出的這種新方法告訴這些細(xì)胞暫停下來,，而不是殺死它們。
論文通信作者Wendell Lim博士重點開展關(guān)于構(gòu)建一種細(xì)胞工具箱---剎車系統(tǒng),、油門和方向盤---方面的細(xì)胞工程研究以便科學(xué)家們將這種細(xì)胞工具箱整合到生物療法當(dāng)中從而更好地控制這些療法和減少它們的副作用,。
事實證明，細(xì)菌是提供這些工具的良好來源,，它們有一系列機制而使得它們能夠在宿主腸道或口腔內(nèi)惡劣環(huán)境中存活下來,。
這些新的發(fā)現(xiàn)證實兩種細(xì)菌效應(yīng)蛋白---鼠疫桿菌(Yersinia pestis)效應(yīng)蛋白YopH和福氏志賀菌(Shigella flexneri)效應(yīng)蛋白OspF---能夠被用來重新激活細(xì)胞中的有絲分裂原蛋白激酶(mitogen-activated protein kinase, MAPK)途徑和對該途徑進行微調(diào)。已知MAPK途徑在免疫反應(yīng)和調(diào)節(jié)與癌癥相關(guān)的不受控制細(xì)胞生長中發(fā)揮著重要作用,。
研究人員還證實在相同的細(xì)胞中,，OspF蛋白能夠被選擇性地用來靶向幾種MAPK途徑中的一種，并且這種MAPK途徑的活性只能通過新的蛋白合成來加以恢復(fù),，而這又進一步延緩宿主細(xì)胞產(chǎn)生免疫反應(yīng),。(生物谷：Bioon.com)
本文編譯自UCSF team engineers 'safety switches' for immune therapies
doi: 10.1038/nature11259
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PMID:
Bacterial virulence proteins as tools to rewire kinase pathways in yeast and immune cells
Bacterial pathogens have evolved specific effector proteins that, by interfacing with host kinase signalling pathways, provide a mechanism to evade immune responses during infection1, 2. Although these effectors contribute to pathogen virulence, we realized that they might also serve as valuable synthetic biology reagents for engineering cellular behaviour. Here we exploit two effector proteins, the Shigella flexneri OspF protein3 and Yersinia pestis YopH protein4, to rewire kinase-mediated responses systematically both in yeast and mammalian immune cells. Bacterial effector proteins can be directed to inhibit specific mitogen-activated protein kinase pathways selectively in yeast by artificially targeting them to pathway-specific complexes. Moreover, we show that unique properties of the effectors generate new pathway behaviours: OspF, which irreversibly inactivates mitogen-activated protein kinases4, was used to construct a synthetic feedback circuit that shows novel frequency-dependent input filtering. Finally, we show that effectors can be used in T cells, either as feedback modulators to tune the T-cell response amplitude precisely, or as an inducible pause switch that can temporarily disable T-cell activation. These studies demonstrate how pathogens could provide a rich toolkit of parts to engineer cells for therapeutic or biotechnological applications.
