據(jù)美國(guó)物理學(xué)家組織網(wǎng)8月21日?qǐng)?bào)道,，美國(guó)加州大學(xué)洛杉磯分校大衛(wèi)·格芬醫(yī)學(xué)院,、凱斯西儲(chǔ)大學(xué)和塔夫斯大學(xué)等多家研究機(jī)構(gòu)合作，在人體內(nèi)發(fā)現(xiàn)了一種能抵抗艱難梭菌感染的天然防御機(jī)制,。該發(fā)現(xiàn)為治療腸道疾病提供了一種新模式,，并有助于開(kāi)發(fā)治療其他類(lèi)型的腹瀉和非腹瀉型細(xì)菌感染的新方法。相關(guān)研究發(fā)表在8月21日的《自然—醫(yī)學(xué)》雜志網(wǎng)站上,。
艱難梭菌感染是一種普通的腸道疾病,，會(huì)導(dǎo)致腹瀉、大腸炎,、結(jié)腸炎等,，甚至死亡,，常在醫(yī)院中傳染流行。該感染在美國(guó)的發(fā)病率比10年前增加了一倍,，而且新的高毒性菌種的出現(xiàn)也讓治療變得更加困難,。
研究人員解釋說(shuō)，艱難梭菌在繁殖期會(huì)釋放兩種強(qiáng)力毒素,，這些毒素能和InsP6（一種廣泛存在于葉類(lèi)蔬菜和胃腸道中的物質(zhì)）結(jié)合,，然后發(fā)生變形和斷裂，斷裂的碎片能穿透細(xì)胞壁,，導(dǎo)致胃腸道出血性損傷,，引起炎癥反應(yīng)和腹瀉。
研究人員發(fā)現(xiàn),，在感染艱難梭菌后,，人體腸道內(nèi)的細(xì)胞能釋放一種含有亞硝基（-NO）的分子巰基亞硝基化谷胱甘肽（GSNO），該分子能直接占據(jù)毒素的活性基位,，使其喪失活性,，從而遏止了它們穿透和損害腸道細(xì)胞。
“這種天然防御機(jī)制是由人體進(jìn)化而來(lái),，其核心是巰基亞硝基化（SNO）過(guò)程,，該過(guò)程是一種將一氧化氮（NO）和半胱氨酸（cysteine）殘基結(jié)合在一起的蛋白修飾作用。”凱斯西儲(chǔ)大學(xué)轉(zhuǎn)化分子醫(yī)學(xué)研究院的喬納森·斯坦拉說(shuō),，“理解這種毒素滅活機(jī)制的原理,，提供了開(kāi)發(fā)新療法的基礎(chǔ)，讓我們能直接瞄準(zhǔn)毒素,，遏制細(xì)菌感染的傳播,。”
在動(dòng)物實(shí)驗(yàn)中，研究人員用藥物引發(fā)了巰基亞硝基化過(guò)程,，成功阻止了艱難梭菌毒素破壞腸道細(xì)胞,。下一步即將開(kāi)展相關(guān)的人體臨床試驗(yàn)。
“找到新的治療模式抵抗艱難梭菌感染是一個(gè)很大的進(jìn)步,。”論文合著者,、加州大學(xué)洛杉磯分校炎癥性腸道疾病中心主任切羅拉波斯·博斯拉吉斯說(shuō)，“我們通過(guò)基因測(cè)序還發(fā)現(xiàn),，巰基亞硝基化過(guò)程能調(diào)控上百種微生物蛋白,。如果試驗(yàn)成功的話，還能用于治療其他細(xì)菌性疾病,。”(生物谷 Biooon.com)
doi:10.1038/nm.2405
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Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins
Tor C Savidge; Petri Urvil; Numan Oezguen; Kausar Ali; Aproteem Choudhury; Vinay Acharya; Irina Pinchuk; Alfredo G Torres; Robert D English; John E Wiktorowicz; Michael Loeffelholz; Raj Kumar; Lianfa Shi; Weijia Nie; Werner Braun; Bo Herman; Alfred Hausladen; Hanping Feng; Jonathan S Stamler; Charalabos Pothoulakis
The global prevalence of severe Clostridium difficile infection highlights the profound clinical significance of clostridial glucosylating toxins1, 2, 3, 4. Virulence is dependent on the autoactivation of a toxin cysteine protease5, 6, 7, 8, 9, which is promoted by the allosteric cofactor inositol hexakisphosphate (InsP6)10, 11, 12, 13, 14, 15, 16, 17. Host mechanisms that protect against such exotoxins are poorly understood. It is increasingly appreciated that the pleiotropic functions attributed to nitric oxide (NO), including host immunity, are in large part mediated by S-nitrosylation of proteins18, 19. Here we show that C. difficile toxins are S-nitrosylated by the infected host and that S-nitrosylation attenuates virulence by inhibiting toxin self-cleavage and cell entry. Notably, InsP6- and inositol pyrophosphate (InsP7)-induced conformational changes in the toxin enabled host S-nitrosothiols to transnitrosylate the toxin catalytic cysteine, which forms part of a structurally conserved nitrosylation motif. Moreover, treatment with exogenous InsP6 enhanced the therapeutic actions of oral S-nitrosothiols in mouse models of C. difficile infection. Allostery in bacterial proteins has thus been successfully exploited in the evolutionary development of nitrosothiol-based innate immunity and may provide an avenue to new therapeutic approaches.
