肺結(jié)核相關(guān)microRNA研究進(jìn)展

央拉 李長(zhǎng)山

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·綜述·

肺結(jié)核相關(guān)microRNA研究進(jìn)展

央拉 李長(zhǎng)山

肺結(jié)核是一種由結(jié)核分枝桿菌引起的慢性呼吸道傳染病。2012年WHO報(bào)道全球約有1/3人口感染過(guò)結(jié)核分枝桿菌，其中約有1/10感染者最終發(fā)展成為結(jié)核病。我國(guó)是世界上22個(gè)結(jié)核病高負(fù)擔(dān)國(guó)家之一，現(xiàn)有患者約500萬(wàn)例，居世界第二位，因此結(jié)核病已成為我國(guó)公共衛(wèi)生防控的難題。目前，關(guān)于該病的研究主要集中于結(jié)核病易感性基因及機(jī)體免疫防護(hù)等方面。microRNA(miRNA)是真核生物中一類長(zhǎng)度約為22 nt的非編碼的小分子RNA。miRNA已成為近20年來(lái)生物學(xué)研究的焦點(diǎn)，其主要是通過(guò)與靶基因信使RNA的特異性位點(diǎn)結(jié)合，抑制靶基因蛋白的表達(dá)，其在生物發(fā)育時(shí)序調(diào)控和疾病的發(fā)生中起到重要作用。已有很多研究表明miRNA在宿主-致病原的免疫網(wǎng)絡(luò)中發(fā)揮重要作用，同時(shí)也有研究表明miRNA與肺部細(xì)菌性疾病的發(fā)生和發(fā)展相關(guān)，深入研究miRNA在肺結(jié)核疾病的功能，可以為該病的診斷和治療提供新的方向。因此，作者總結(jié)了國(guó)內(nèi)外與肺結(jié)核相關(guān)的miRNA的研究進(jìn)展，希望為肺結(jié)核的預(yù)防、控制和治療提供新的契機(jī)。

結(jié)核, 肺； 微RNAs； 生物學(xué)標(biāo)記

肺結(jié)核是一種由單一致病菌——結(jié)核分枝桿菌(Mycobacteriumtuberculosis，Mtb)引起的慢性傳染病。鑒于其全球極高的發(fā)病率和致死率，圍繞肺結(jié)核的發(fā)病機(jī)理及機(jī)體的免疫防護(hù)已有很多研究報(bào)道。流行病學(xué)統(tǒng)計(jì)發(fā)現(xiàn)，在Mtb感染人群中僅有10%的人群會(huì)有臨床癥狀[1]，這一發(fā)現(xiàn)提示個(gè)體差異可能與結(jié)核病易感性、個(gè)體免疫抑制等相關(guān)。目前已經(jīng)發(fā)現(xiàn)，個(gè)體對(duì)結(jié)核病易感性的差異部分由多個(gè)宿主基因，如自然抗性相關(guān)巨噬細(xì)胞蛋白1基因(natural resistance associated macrophage protein 1, NRAMP1)、甘露糖結(jié)合凝集素基因(mannose binding lectin, MBL)和維生素D受體基因(vitamin-D receptor，VDR)等決定[2-3]。而在免疫抑制方面，流行病學(xué)統(tǒng)計(jì)發(fā)現(xiàn)Mtb感染后AIDS患者更容易臨床發(fā)病[4]，這提示機(jī)體的免疫抑制在肺結(jié)核發(fā)病過(guò)程中發(fā)揮重要作用。

Mtb是胞內(nèi)感染菌，當(dāng)其侵入呼吸道后，巨噬細(xì)胞表面Toll樣受體首先識(shí)別Mtb，釋放腫瘤壞死因子(tumor necrosis factor, TNF)α(TNF-α)，其可以顯著抑制Mtb在巨噬細(xì)胞中的生長(zhǎng)[5]。同時(shí)巨噬細(xì)胞作為抗原遞呈細(xì)胞遞呈抗原，使周圍T淋巴細(xì)胞致敏激活核轉(zhuǎn)錄因子κB(NF-κB)信號(hào)通路釋放前炎癥細(xì)胞因子(proinflammatory cytokines)，如γ干擾素(interferon-γ,INF-γ)、白細(xì)胞介素(interleukin，IL)-1β(IL-1β)和IL-6等[5]。INF-γ 是主要的前炎癥細(xì)胞因子[6]，該因子可以激活巨噬細(xì)胞，使吞噬作用加強(qiáng)，導(dǎo)致活性氧中介物和活性氮中介物的產(chǎn)生，從而將病菌殺死。在小鼠模型和患者中都證明IFN-γ可以很好保護(hù)機(jī)體免受結(jié)核分枝桿菌感染[4, 7]。IL-1β和IL-6在宿主抵抗結(jié)核分枝桿菌感染過(guò)程中起到保護(hù)作用[8-9]。

microRNA(miRNA)是一類長(zhǎng)度約為22 nt的非編碼的小分子RNA。自從20世紀(jì)90年代發(fā)現(xiàn)以來(lái)，miRNA的功能和作用的研究已經(jīng)成為近年來(lái)生物學(xué)界關(guān)注的焦點(diǎn)。miRNA主要通過(guò)結(jié)合mRNA 3′UTR 非翻譯區(qū)的含有特定序列的位點(diǎn)，來(lái)抑制蛋白的表達(dá)。這些特定的序列被稱為種子序列(seed sequence)[10]。除了seed sequence外的其余序列可以不完全互補(bǔ)，正是這種不完全互補(bǔ)，使得一個(gè)miRNA可以結(jié)合并調(diào)控許多基因，而某一個(gè)miRNA往往會(huì)調(diào)控一個(gè)信號(hào)通路的多個(gè)基因，使得它們具有功能的特異性[11]。至今為止，miRNA可以調(diào)控包括發(fā)育、細(xì)胞增殖、細(xì)胞凋亡、器官發(fā)生、腫瘤發(fā)生和免疫在內(nèi)的若干個(gè)生物途徑[12]。目前，已有很多研究報(bào)道m(xù)iRNA在宿主-致病原作用網(wǎng)絡(luò)中發(fā)揮作用[13-14]。比如，miRNA-155在先天性免疫和獲得性免疫應(yīng)答過(guò)程中都發(fā)揮作用[15]，同時(shí)在T細(xì)胞介導(dǎo)細(xì)胞免疫調(diào)控幽門螺旋桿菌感染過(guò)程中也發(fā)揮重要作用[16]；miRNA-181a能增強(qiáng)T細(xì)胞對(duì)抗原的免疫反應(yīng)[17]；當(dāng)機(jī)體受到沙門菌感染時(shí)，let-7 miRNA家族可以抑制IL-6和IL-10的表達(dá)[18]；當(dāng)機(jī)體Toll樣受體激活時(shí)，可以誘導(dǎo)miRNA-147表達(dá)從而調(diào)控巨噬細(xì)胞免疫反應(yīng)[19]。

之前已有研究表明在臨床發(fā)病的結(jié)核病患者和健康人的巨噬細(xì)胞和自然殺傷細(xì)胞中存在顯著的基因表達(dá)差異[20-21]。而miRNA往往會(huì)調(diào)控一個(gè)信號(hào)通路的多個(gè)基因，并且研究發(fā)現(xiàn)miRNA在宿主-致病原作用網(wǎng)絡(luò)中發(fā)揮作用。因此，筆者將介紹目前報(bào)道的結(jié)核病分子病理相關(guān)的miRNA，以及探討其作為結(jié)核病生物標(biāo)志物的可能性。

miRNA可調(diào)控機(jī)體對(duì)Mtb的免疫反應(yīng)

目前，關(guān)于結(jié)核病分子病理相關(guān)的miRNA研究主要圍繞在結(jié)核病患者中高表達(dá)的miRNA進(jìn)行。這些在臨床發(fā)病患者中高表達(dá)的miRNA，往往是抑制機(jī)體對(duì)Mtb的免疫反應(yīng)。這里，筆者簡(jiǎn)單介紹一下這些miRNA在結(jié)核病患者機(jī)體免疫過(guò)程中的作用。

1. miRNA-21：Sheedy等[22]最早研究發(fā)現(xiàn)，miRNA-21可以抑制前炎癥因子PDCD4的表達(dá)，而PDCD4可以激活NF-κB信號(hào)通路增強(qiáng)機(jī)體對(duì)免疫原的免疫反應(yīng)。而2012年Wu等[23]和Kumar等[24]兩個(gè)研究組都發(fā)現(xiàn)miRNA-21在Mtb感染的巨噬細(xì)胞中顯著高表達(dá)。同時(shí)，Kumar等[24]研究組還發(fā)現(xiàn)miRNA-21通過(guò)抑制IL-12的表達(dá)，從而抑制宿主對(duì)Mtb的Th1免疫反應(yīng)。因此，Mtb很可能利用miRNA-21逃脫機(jī)體的免疫反應(yīng)從而使患者致病。

2. miRNA-29：已有多項(xiàng)研究表明，在Mtb感染后患者miRNA-29表達(dá)水平升高[25-27]。研究發(fā)現(xiàn)，miRNA-29通過(guò)抑制p85α和CDC42蛋白表達(dá)激活p53引發(fā)細(xì)胞凋亡[28-29]。因此，當(dāng)機(jī)體受到Mtb感染后，T細(xì)胞內(nèi)miRNA-29表達(dá)水平升高，誘發(fā)T細(xì)胞凋亡，從而受感染者體內(nèi)Mtb大量繁殖，導(dǎo)致個(gè)體發(fā)病。Ma 等[30]研究發(fā)現(xiàn)，miRNA-29通過(guò)結(jié)合INF-γ mRNA的3′UTR而抑制INF-γ的表達(dá)；INF-γ表達(dá)水平降低同樣將導(dǎo)致個(gè)體更容易感染Mtb。

3. miRNA-125b：Rajaram等[31]研究發(fā)現(xiàn)，miRNA-125b可以直接結(jié)合TNF mRNA的3′UTR，從而抑制TNF的表達(dá)。Huang等[32]則在新生嬰兒?jiǎn)魏思?xì)胞研究中發(fā)現(xiàn)，其胞內(nèi)TNF-a蛋白水平與miRNA-125b呈負(fù)相關(guān)；在新生嬰兒?jiǎn)魏思?xì)胞中人為轉(zhuǎn)入miRNA-125b的前體，可以顯著降低TNF-a蛋白水平。這兩個(gè)研究都提示miRNA-125b可以負(fù)調(diào)控TNF蛋白水平。與INF-γ類似，TNF蛋白水平下調(diào)同樣將導(dǎo)致個(gè)體更容易感染Mtb。

4. miRNA-144*：miRNA-144*同樣被發(fā)現(xiàn)在肺結(jié)核患者體內(nèi)高表達(dá)。Liu等[33]在研究中將miRNA-144*前體人為轉(zhuǎn)入T細(xì)胞中，結(jié)果顯示外源過(guò)表達(dá)miRNA-144*將顯著抑制T細(xì)胞產(chǎn)生INF-γ和TNF-α，并導(dǎo)致T細(xì)胞增殖能力顯著降低。因此，miRNA-144*表達(dá)水平升高，一方面抑制T細(xì)胞增殖，另外還可以抑制T細(xì)胞產(chǎn)生INF-γ和TNF-α，從而導(dǎo)致感染Mtb的個(gè)體發(fā)病。

5. miRNA-155：miRNA-155已被研究證實(shí)參與機(jī)體先天性免疫和獲得性免疫2個(gè)過(guò)程。在細(xì)菌感染后的先天性免疫中，多種免疫因子如TNF-α、IL-1β等都可以誘導(dǎo)miRNA-155的表達(dá)，增強(qiáng)機(jī)體的免疫反應(yīng)。Tili等[34]則研究發(fā)現(xiàn)，當(dāng)單核巨噬細(xì)胞受到細(xì)菌脂多糖刺激時(shí)，TNF-α的水平會(huì)顯著提高并伴隨miRNA-155表達(dá)水平上調(diào)。而miRNA-155表達(dá)水平上調(diào)又會(huì)提高TNF-α的表達(dá)水平，但目前這一正反饋機(jī)制如何實(shí)現(xiàn)尚未闡明。在獲得性免疫調(diào)節(jié)方面，Rodriguez等[15]和Thai等[35]的研究都證明miRNA-155缺陷的小鼠，其B細(xì)胞和T細(xì)胞免疫都受到顯著影響。miRNA-155缺陷小鼠，其免疫系統(tǒng)不能有效地呈遞抗原激活T細(xì)胞，進(jìn)而使得T細(xì)胞傾向于向Th2細(xì)胞分化。可以發(fā)現(xiàn)，miRNA-155可能在機(jī)體免疫反應(yīng)過(guò)程中作為一個(gè)保護(hù)性的miRNA控制炎癥反應(yīng)所造成的組織損傷。

6. miRNA-223：Wang 等[36]研究發(fā)現(xiàn)，肺結(jié)核患者外周血液?jiǎn)魏肆＜?xì)胞中miRNA-223表達(dá)水平顯著升高。miRNA-223功能缺失小鼠顯示其體內(nèi)粒性白細(xì)胞數(shù)目增多，并且形態(tài)上這些粒性白細(xì)胞更加成熟，其對(duì)激活刺激更加敏感[37]。肺結(jié)核患者發(fā)病時(shí)，中性粒細(xì)胞會(huì)浸入肺部維持基礎(chǔ)免疫并釋放趨化因子如CXCL2、CCL3、IL-6，而這些趨化因子則會(huì)招募更多的中性粒細(xì)胞到達(dá)感染位置從而消除病菌[38-39]。Dorhoi等[40]研究發(fā)現(xiàn)，miRNA-223可以靶向這些化學(xué)引誘物[40]。因此，一種可能的機(jī)制是miRNA-223抑制趨化因子的表達(dá)，從而減弱中性粒細(xì)胞對(duì)Mtb的吞噬作用，使得感染個(gè)體更容易臨床發(fā)病。

7. miRNA-582-5p：淋巴細(xì)胞凋亡是宿主抵抗Mtb的一種免疫機(jī)制[41-42]。Liu 等[43]研究發(fā)現(xiàn)，結(jié)核病患者外周血單核粒細(xì)胞凋亡比例顯著低于健康人群。通過(guò)基因芯片檢測(cè)，發(fā)現(xiàn)在單核粒細(xì)胞中miRNA-582-5p顯著提高。在THP-1單核細(xì)胞中外源轉(zhuǎn)入miRNA-582-5p類似物，使得細(xì)胞凋亡比例顯著降低。信息生物學(xué)分析及多種實(shí)驗(yàn)驗(yàn)證，F(xiàn)OXO1(forkhead box O1)是miRNA-582-5p的靶向基因[43]。已有研究證明FOXO1可以促進(jìn)細(xì)胞凋亡[44]。因此，miRNA-582-5p通過(guò)抑制FOXO1蛋白表達(dá)，降低單核粒細(xì)胞的細(xì)胞凋亡，從而減弱機(jī)體對(duì)Mtb的免疫反應(yīng)。

綜上所述，結(jié)核病患者高表達(dá)的miRNA多數(shù)會(huì)負(fù)調(diào)控機(jī)體對(duì)Mtb的免疫反應(yīng)，從而使被感染個(gè)體更容易發(fā)病。而miRNA-155則在機(jī)體內(nèi)發(fā)揮保護(hù)性作用，當(dāng)機(jī)體受到Mtb感染后，TNF-α和miRNA-155表達(dá)水平都會(huì)顯著提高，miRNA-155的升高又會(huì)正反饋調(diào)控TNF-α的表達(dá)，從而增強(qiáng)機(jī)體對(duì)Mtb的免疫反應(yīng)。因此，不同的miRNA在結(jié)核病免疫調(diào)控中發(fā)揮不同的作用，其分子機(jī)制還有待進(jìn)一步深入的研究。

miRNA作為結(jié)核病診斷生物標(biāo)志物的可能性

肺結(jié)核早期診斷是有效控制和治療該病的關(guān)鍵[45]。目前，關(guān)于肺結(jié)核的臨床診斷手段主要為痰細(xì)菌學(xué)檢查和胸部X線攝片[46]。肺結(jié)核診斷最直接的證據(jù)是從患者的痰中分離培養(yǎng)Mtb，但是以細(xì)菌培養(yǎng)為依據(jù)的細(xì)菌學(xué)診斷對(duì)實(shí)驗(yàn)環(huán)境及技術(shù)人員要求較高，并且Mtb培養(yǎng)耗時(shí)較長(zhǎng)(長(zhǎng)達(dá)4～8周)，因此結(jié)核病診斷仍以顯微鏡下痰涂片診斷為主。對(duì)于肺結(jié)核的防控需要建立一種快速、準(zhǔn)確、安全、簡(jiǎn)便和低成本的新型診斷方法。

理想的生物標(biāo)志物應(yīng)具有性質(zhì)穩(wěn)定、易于檢測(cè)及敏感度高等特征。研究發(fā)現(xiàn)，血清中miRNA可以穩(wěn)定存在而不被核糖核酸酶(ribonuclease, RNase)降解[47]，并且在多種疾病研究中都發(fā)現(xiàn)“某些miRNA在健康組和對(duì)照組中存在顯著變化”。因此，血清中特異性的miRNA檢測(cè)已成為一種新型疾病診斷標(biāo)志物。由于一個(gè)miRNA可以結(jié)合并調(diào)控多個(gè)基因，因此對(duì)于單一疾病的診斷需要結(jié)合多個(gè)標(biāo)志性miRNAs才能得到較為準(zhǔn)確的診斷結(jié)果。目前，已有多種疾病選取miRNA作為疾病的診斷標(biāo)志物，例如：對(duì)于非小細(xì)胞肺癌(NSCLC)和小細(xì)胞肺癌(SCLC)都可以通過(guò)多種miRNA加以鑒定[48-49]；miRNA-145和miRNA-451組合是較好的檢測(cè)乳腺癌的分子標(biāo)志物，等等。那么，是否可以選取在肺結(jié)核患者中高表達(dá)的miRNAs作為該病的分子診斷標(biāo)志物呢？

Fu等[26]曾研究報(bào)道過(guò)與健康人群相比，活動(dòng)性肺結(jié)核患者血清內(nèi)有59個(gè)miRNA高表達(dá)；而Qi等[50]在2012年則發(fā)現(xiàn)肺結(jié)核患者血清內(nèi)有90個(gè)miRNA高表達(dá)。通過(guò)交叉比對(duì)2篇文獻(xiàn)的研究結(jié)果，筆者梳理出總共有8個(gè)miRNA在兩項(xiàng)研究的結(jié)果中都呈現(xiàn)高表達(dá)，分別為：miRNA-29a、miRNA-744、miRNA-30c、miRNA-146a、miRNA-433、miRNA-93、miRNA-103和miRNA-let-7g。通過(guò)交叉比對(duì)，可以排除由于個(gè)體等偶然因素獲得的假陽(yáng)性結(jié)果，通過(guò)擴(kuò)大樣本量驗(yàn)證并最終確立幾個(gè)miRNA作為肺結(jié)核的分子診斷標(biāo)志物，從而為肺結(jié)核的診治提供一種快速簡(jiǎn)便的新型分子診斷方法。

總結(jié)和展望

筆者總結(jié)了近幾年報(bào)道的與肺結(jié)核相關(guān)的miRNA及其參與肺結(jié)核患者機(jī)體免疫的分子機(jī)制，通過(guò)交叉比對(duì)兩項(xiàng)研究結(jié)果，筆者初步獲得8個(gè)miRNA作為肺結(jié)核可能的分子診斷標(biāo)志物，但是仍需要進(jìn)一步的實(shí)驗(yàn)驗(yàn)證?？傮w來(lái)說(shuō)，國(guó)內(nèi)肺結(jié)核領(lǐng)域miRNA的研究仍集中于肺結(jié)核患者差異表達(dá)的miRNA的篩選工作，通過(guò)這些研究已發(fā)現(xiàn)多個(gè)在肺結(jié)核患者中差異表達(dá)的miRNAs，為進(jìn)一步開(kāi)展肺結(jié)核診治的研究工作奠定了基礎(chǔ)；而目前對(duì)于篩選獲得的候選miRNA如何參與調(diào)控機(jī)體免疫反應(yīng)的分子機(jī)制方面的研究則不多見(jiàn)。

結(jié)合其他領(lǐng)域miRNA的研究思路，miRNA的研究主要有兩大方向：(1)miRNA的表達(dá)調(diào)控。例如，Mtb感染細(xì)胞后，機(jī)體如何提高miRNA-21、miRNA-29等miRNA的表達(dá)。通過(guò)生物信息學(xué)分析miRNA的啟動(dòng)子，獲得可能的轉(zhuǎn)錄因子，進(jìn)而深入研究機(jī)體是如何轉(zhuǎn)錄調(diào)控miRNA的表達(dá)。(2)miRNA的靶向基因研究。miRNA在體內(nèi)主要是通過(guò)在轉(zhuǎn)錄后水平調(diào)控靶向基因的表達(dá)發(fā)揮生理功能。通過(guò)基因芯片技術(shù)結(jié)合生物信息學(xué)分析獲得miRNA調(diào)控的靶向基因，將有助于我們深入研究miRNA參與調(diào)控機(jī)體免疫反應(yīng)的分子機(jī)制。另外，目前的研究報(bào)道主要關(guān)注肺結(jié)核患者中高表達(dá)的miRNA，實(shí)際上那些在結(jié)核病患者中被下調(diào)的miRNA可能對(duì)于肺結(jié)核的預(yù)防或治療更有實(shí)際意義，這也是今后肺結(jié)核防治領(lǐng)域miRNA研究的一個(gè)方向。

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(本文編輯：薛愛(ài)華)

Progress of pulmonary tuberculosis related microRNAs

YANG La, LI Chang-shan.

Laboratory of Microbiology, College of Medicine, Tibet University, Lhasa 850000，China

LI Chang-shan, Email: changshanli058@outlook.com

Pulmonary tuberculosis is chronic respiratory infectious disease caused byMycobacteriumtuberculosis(Mtb). According to the 2012 World Health Organization (WHO) report, about one third of the global population was infected byMycobacteriumtuberculosis, of which one-tenth people eventually developed with TB disease. China is one of the 22 TB high-burden countries in the world, has about 5 million patients, ranking second in the world. Therefore, TB has become a public health issue in China. Current research is mainly focused on tuberculosis susceptibility genes and immune protection. MicroRNA (miRNA) is a length of about 22 in eukaryotes NT of small non-coding RNA molecules. MiRNA has become the focus of biological research in nearly 20 years, which is linked with the specific site of the target gene mRNA, inhibited the expression of target genes for proteins, regulated its biological development and plays an important role in the development of the disease. Many studies have shown that miRNA play an important role in host-pathogenic immune networks, are also associated with the occurrence and development of bacterial diseases of the lungs. In-depth of miRNA function in TB disease could provide new direction for the diagnosis and treatment of the disease. Therefore, the author summarizes the advances in miRNA associated with tuberculosis, which could create opportunities for TB prevention, diagnosis and treatment.

Tuberculosis, pulmonary； microRNAs； Biological markers

10.3969/j.issn.1000-6621.2015.02.015

850000 拉薩，西藏大學(xué)醫(yī)學(xué)院基礎(chǔ)部病原生物學(xué)教研室

李長(zhǎng)山，Email: changshanli058@outlook.com

2014-09-15)