近日,，Cell旗下著名雜志Cell Host & Microbe在線刊登了哈佛醫(yī)學(xué)院研究人員的最新研究成果“Host Translational Inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an Immune Response in Caenorhabditis elegans,，”，文章中,，研究者研究了銅綠假單胞菌（綠膿桿菌）觸發(fā)秀麗隱桿線蟲腸道天然免疫力的分子機(jī)制。
腸道上皮細(xì)胞（IECs）長期暴露于無害和有害的微生物群落中,，為了引起合適的免疫反應(yīng),，腸道上皮細(xì)胞必須區(qū)分出哪種細(xì)菌致病,，哪種細(xì)菌是共生無害的。目前,，對于IECs如何識別并且和致病微生物的毒力因子發(fā)生免疫反應(yīng),，我們尚不清楚。在本研究中,，來自哈佛醫(yī)學(xué)院的研究者Frederick M.Ausubel用秀麗隱桿線蟲(C.elegans)來研究IECs識別致病菌的分子機(jī)理,。秀麗隱桿線蟲缺少專門的免疫細(xì)胞，因此IECs完全充當(dāng)了C.elegans抵御綠膿桿菌的主要防御系統(tǒng),，當(dāng)銅綠假單胞菌PA14積累在C.elegans腸臟處時(shí),，可以引發(fā)宿主的機(jī)體損傷、抗微生物相關(guān)基因的表達(dá)量增加以及最終殺死線蟲宿主,。
近日的一些研究數(shù)據(jù)顯示,，相比野生型菌株，加熱滅活的綠膿桿菌或者毒力降低的突變體菌株可以誘導(dǎo)宿主基因的低水平表達(dá),，這就暗示了C.elegans的免疫能力的激活是由于綠膿桿菌感染后通過DAMPs（damage-associated molecular patterns,，損傷相關(guān)的分子樣式）途徑來產(chǎn)生的?；谶@些數(shù)據(jù),，作者假設(shè)，由于單一的綠膿桿菌因子產(chǎn)生的DAMP信號分子途徑或者宿主的修飾有可能對于觸發(fā)C.elegans免疫系統(tǒng)的產(chǎn)生是足夠的,。
ToxA（外毒素A）是90%以上臨床綠膿桿菌所表達(dá)的一種細(xì)菌毒素,，當(dāng)C.elegans感染綠膿桿菌后，ToxA可以抑制C.elegans體內(nèi)的蛋白質(zhì)合成,，在研究中,，研究者給出了一些證據(jù)，這些證據(jù)顯示,，C.elegans可以通過檢測并且識別ToxA介導(dǎo)的翻譯抑制劑來識別ToxA毒素,，這種識別能力可以激活蠕蟲體內(nèi)部分依賴于免疫系統(tǒng)的潛在的轉(zhuǎn)錄應(yīng)答，而且可以激活諸如ZIP-2,，PMK-1,，MAPK，F(xiàn)SHR-1等抵抗綠膿桿菌感染的免疫能力,。研究證據(jù)闡釋了銅綠假單胞菌的毒力因子可以激活C.elegans一系列免疫系統(tǒng)基因的表達(dá),，從而使得C.elegans可以抵御銅綠假單胞菌的感染。（生物谷：T.Shen編譯）
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doi:10.1016/j.chom.2012.02.007
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PMID:
Host Translational Inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an Immune Response in Caenorhabditis elegans
Deborah L. McEwan, Natalia V. Kirienko, Frederick M. Ausubel
Intestinal epithelial cells are exposed to both innocuous and pathogenic microbes, which need to be distinguished to mount an effective immune response. To understand the mechanisms underlying pathogen recognition, we investigated how Pseudomonas aeruginosa triggers intestinal innate immunity in Caenorhabditis elegans, a process independent of Toll-like pattern recognition receptors. We show that the P. aeruginosa translational inhibitor Exotoxin A (ToxA), which ribosylates elongation factor 2 (EF2), upregulates a significant subset of genes normally induced by P. aeruginosa. Moreover, immune pathways involving the ATF-7 and ZIP-2 transcription factors, which protect C. elegans from P. aeruginosa, are required for preventing ToxA-mediated lethality. ToxA-responsive genes are not induced by enzymatically inactive ToxA protein but can be upregulated independently of ToxA by disruption of host protein translation. Thus, C. elegans has a surveillance mechanism to recognize ToxA through its effect on protein translation rather than by direct recognition of either ToxA or ribosylated EF2.
