汪小歡，鄒鵬，黎媛，陸路

1. 上海市(復(fù)旦大學(xué)附屬)公共衛(wèi)生臨床中心，上海 201508； 2. 復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院醫(yī)學(xué)分子病毒學(xué)教育部/衛(wèi)生部重點(diǎn)實(shí)驗(yàn)室，上海 200032

·特約專稿·

寨卡病毒引發(fā)小頭癥？關(guān)系越確定，防治越迫切！

汪小歡1,2，鄒鵬1，黎媛1，陸路1,2

1. 上海市(復(fù)旦大學(xué)附屬)公共衛(wèi)生臨床中心，上海 201508； 2. 復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院醫(yī)學(xué)分子病毒學(xué)教育部/衛(wèi)生部重點(diǎn)實(shí)驗(yàn)室，上海 200032

自2015年初至今，寨卡病毒(Zika virus，ZIKV)以巴西為首先后在數(shù)十個(gè)國(guó)家和地區(qū)暴發(fā)流行。幾乎同時(shí)，與日俱增的小頭癥患兒使全球?qū)Υ讼萑刖锠顟B(tài)。目前，全球正在積極探索ZIKV感染所引發(fā)的各種神經(jīng)系統(tǒng)疾病。在越來越多證據(jù)表明在細(xì)胞水平和動(dòng)物模型中ZIKV能直接損傷胚胎腦部發(fā)育的同時(shí)，ZIKV感染者的防治需求也越來越迫切。本文從ZIKV的流行病學(xué)、與小頭畸形因果關(guān)系的研究進(jìn)展及其預(yù)防疫苗和治療藥物的研究現(xiàn)狀等方面進(jìn)行概述。

寨卡病毒；小頭癥；流行病學(xué)；預(yù)防疫苗；治療藥物

近期，寨卡病毒(Zika virus，ZIKV)迅速蔓延。2015年3月，巴西巴伊亞地區(qū)(東北地區(qū))首先報(bào)道了24例ZIKV感染者，此后越來越多的ZIKV疑似感染者出現(xiàn)。至同年5月，巴西衛(wèi)生部確證了ZIKV的本土傳播[1-2]。2015年10月，研究者在巴西伯南布哥州(東北地區(qū))觀察到當(dāng)?shù)匦☆^畸形的新生兒(小頭癥患兒)數(shù)目異常增多。1個(gè)月后，巴西衛(wèi)生部公告該國(guó)東北地區(qū)的ZIKV感染與小頭癥患兒驟增有直接關(guān)系[3]。愈演愈烈的ZIKV流行趨勢(shì)及孕婦感染者的嚴(yán)重不良后果使全球?qū)Υ讼萑刖锠顟B(tài)。因此，在逐步探索ZIKV感染與小頭畸形關(guān)系的同時(shí)，相應(yīng)的預(yù)防措施和治療方案對(duì)緩解甚至避免當(dāng)前ZIKV流行的嚴(yán)峻形勢(shì)至關(guān)重要。

1 ZIKV流行病學(xué)

1947年，ZIKV作為黃病毒科黃病毒屬的一員首次被發(fā)現(xiàn)，研究人員從發(fā)熱的恒河猴血清中分離出第1株ZIKV，7年后才有其感染人類的報(bào)道[4-5]。進(jìn)入21世紀(jì)以來，ZIKV不斷暴發(fā)流行，2007年波及了雅浦島等數(shù)個(gè)島嶼，2013—2014年感染了法屬波利尼西亞的數(shù)萬居民[6-7]。2014年，復(fù)活節(jié)島的本地ZIKV流行(感染者在潛伏期內(nèi)無ZIKV流行地區(qū)旅行史)標(biāo)志著ZIKV開始波及美洲地區(qū)[8]。同時(shí)期，亞洲地區(qū)也報(bào)道了ZIKV散在感染病例[9-10]。

自2015年4月，ZIKV于半年內(nèi)蔓延了至少巴西14個(gè)地區(qū)，感染病例高達(dá)130萬[11]。哥倫比亞也同時(shí)報(bào)道了ZIKV的本土傳播及至少5 000多例疑似感染病例[11-12]。2016年11月18日，世界衛(wèi)生組織(World Health Organization，WHO)更新了ZIKV相關(guān)形勢(shì)報(bào)道，自2015年起累計(jì)69個(gè)國(guó)家和地區(qū)出現(xiàn)了ZIKV感染病例，包括泰國(guó)、韓國(guó)、越南、印度尼西亞、馬來西亞和新加坡等亞洲國(guó)家[13]。2016年11月21日，新加坡國(guó)家環(huán)境局公布新加坡ZIKV累計(jì)感染病例已達(dá)453例[14]。中國(guó)也在2016年2月出現(xiàn)了輸入性ZIKV感染病例[15]。亞洲諸多國(guó)家陸續(xù)出現(xiàn)ZIKV感染病例，使得ZIKV感染形勢(shì)不斷升級(jí)，引起了國(guó)際社會(huì)的高度關(guān)注。ZIKV是一種蟲媒病毒，能不斷發(fā)生突變而更好地侵襲傳播媒介和宿主。伊蚊作為ZIKV的傳播媒介，幾乎存在于美洲各國(guó)家，因此ZIKV很可能在整個(gè)美洲傳播。巴西首次報(bào)道ZIKV感染病例半年后，研究者注意到當(dāng)?shù)匦☆^癥患兒數(shù)目與日俱增，僅至2016年2月中旬就已超過4 300例[16]。早在2013—2014年法屬波利尼西亞ZIKV暴發(fā)流行期間，研究者就觀察到流行地區(qū)小頭癥患兒和格林-巴利綜合征(Guillain-Barré syndrome，GBS)患者數(shù)量顯著增加[17-18]。此外，越來越多的證據(jù)表明ZIKV感染是引發(fā)小頭癥和GBS的可能原因，從而引起全球范圍對(duì)ZIKV的廣泛關(guān)注。2016年2月1日，WHO將ZIKV相關(guān)小頭癥等中樞神經(jīng)系統(tǒng)病變列為國(guó)際突發(fā)公共衛(wèi)生事件[19]。綜上所述，ZIKV流行病學(xué)的時(shí)間軸如圖1所示。

圖1 ZIKV流行病學(xué)時(shí)間軸

Fig.1 The timeline of Zika virus epidemiology

2 ZIKV與小頭癥相關(guān)性研究：從相關(guān)到因果

在ZIKV感染引發(fā)的各種神經(jīng)系統(tǒng)疾病中，小頭癥最先引起各國(guó)研究者的注意。小頭癥定義為頭圍(經(jīng)額枕測(cè)量)小于特定年齡和性別平均值的2個(gè)標(biāo)準(zhǔn)差[20]，是一種大腦皮質(zhì)神經(jīng)祖細(xì)胞增殖障礙和死亡所致的神經(jīng)系統(tǒng)發(fā)育異常性疾病，大部分患者會(huì)表現(xiàn)出不同程度的智力障礙[21]。

小頭癥病因包括遺傳因素、環(huán)境因素和母體因素。在母體因素中，孕婦感染病毒可能導(dǎo)致胎兒發(fā)生小頭癥，其中巨細(xì)胞病毒或風(fēng)疹病毒感染均有導(dǎo)致胎兒小頭畸形的可能[22-24]。從病原學(xué)角度來看，ZIKV也可能是導(dǎo)致小頭癥的病原體之一。分析此次ZIKV在巴西的流行情況，從出現(xiàn)大量ZIKV感染者到小頭癥患兒顯現(xiàn)的時(shí)間大概是半年[25]，這也正是孕婦能通過產(chǎn)前B超檢查胎兒顱骨發(fā)育是否正常的合適時(shí)間。因此，從時(shí)間的推移來說，ZIKV感染孕婦很可能引發(fā)胎兒小頭畸形。此外，巴西ZIKV本土傳播和小頭癥患兒驟增的地區(qū)均在東北地區(qū)，兩者也具有空間一致性。

在理論分析支持的同時(shí)，研究者積極進(jìn)行了ZIKV導(dǎo)致小頭癥的實(shí)驗(yàn)研究。Tang等揭示，ZIKV可通過增加細(xì)胞死亡和紊亂細(xì)胞周期來直接攻擊人類神經(jīng)祖細(xì)胞，進(jìn)而阻礙大腦正常發(fā)育[26]。Lazear團(tuán)隊(duì)比較5種ZIKV毒株：MR766(Uganda，1947)、Dakar 41519(Senegal，1984)、Dakar 41667(Senegal，1984)、Dakar 41671(Senegal，1984)和H/PF/2013(French Polynesia，2013)[4,27-29]，發(fā)現(xiàn)H/PF/2013毒株具有更強(qiáng)的毒力[30]。而Tang等在研究中使用的是MR766毒株，非近年ZIKV流行毒株，不能因此認(rèn)為小頭癥患兒增加是由于ZIKV毒力變異的結(jié)果。相比一般體外實(shí)驗(yàn)，類器官3D模型能模仿人類器官形成過程，在研究ZIKV與小頭癥關(guān)系中受到各國(guó)研究者的青睞。2016年5月，巴西Garcez及其同事利用人類誘導(dǎo)多能干細(xì)胞(induced pluripotent stem cell，iPSC)培養(yǎng)成神經(jīng)干細(xì)胞(neural stem cell，NSC)、神經(jīng)球和大腦類器官，以神經(jīng)球呈現(xiàn)神經(jīng)形成過程的早期特征，以大腦類器官模擬胎兒第一孕期大腦新皮質(zhì)包括基因表達(dá)和皮質(zhì)分層細(xì)胞及其分子事件。結(jié)果證實(shí)ZIKV誘導(dǎo)iPSC來源的NSC死亡，阻礙神經(jīng)球形成和發(fā)展，從而減慢大腦類器官成長(zhǎng)[31]。美國(guó)Cauchemez等將ZIKV作用于不同日齡(14、28和80 d)的類器官以模擬ZIKV對(duì)不同胎齡大腦的作用，通過觀察類器官的特征變化，發(fā)現(xiàn)即使早期階段短暫接觸低劑量的ZIKV，類器官也會(huì)產(chǎn)生長(zhǎng)期日益嚴(yán)重的后果，這與第一孕期感染ZIKV危險(xiǎn)性最高的臨床發(fā)現(xiàn)一致[32]。

此外，各國(guó)研究者還致力于通過建立體內(nèi)模型來研究ZIKV與小頭癥的因果關(guān)系。Rossi等用α干擾素(interferon α，IFN-α)受體缺陷小鼠建立ZIKV感染模型，小鼠大腦在感染后第3天檢測(cè)到ZIKV，感染后第6天觀察到大腦神經(jīng)病變[33]。2016年5月，中國(guó)科學(xué)院許執(zhí)恒和軍事醫(yī)學(xué)科學(xué)院秦成峰的研究團(tuán)隊(duì)建立了ZIKV感染胎鼠模型，直觀呈現(xiàn)了ZIKV感染后胎鼠大腦變薄的皮質(zhì)層和更加稀疏的腦室及腦室下帶[34]，但該模型沒能實(shí)現(xiàn)對(duì)ZIKV感染胎鼠出生后連續(xù)長(zhǎng)時(shí)期的觀察。隨后，Goodfellow等成功建立了ZIKV感染雞胚模型，并以此呈現(xiàn)了ZIKV的高劑量致死效應(yīng)和類似小頭癥的中樞神經(jīng)系統(tǒng)發(fā)育障礙的漸進(jìn)過程[35]。與小鼠模型相比，雞胚模型實(shí)現(xiàn)了對(duì)ZIKV感染后的胚胎更長(zhǎng)時(shí)間的觀察。

也有研究者嘗試從自身免疫方向?qū)IKV感染與小頭癥關(guān)系進(jìn)行探索。胎兒的ZIKV暴露能引發(fā)機(jī)體抗病毒免疫反應(yīng)，同時(shí)會(huì)針對(duì)體內(nèi)共同存在的蛋白多肽發(fā)生交叉反應(yīng)，一旦這些機(jī)體蛋白被攻擊，相關(guān)的小頭癥、眼部異常、腦部鈣化及神經(jīng)發(fā)育障礙隨之發(fā)生。Lucchese及其同事分析了ZIKV與人類小頭癥相關(guān)的共同蛋白多肽，并利用免疫抗原決定簇?cái)?shù)據(jù)庫(Immune Epitope Database，IEDB)了解這些共同蛋白多肽引發(fā)機(jī)體免疫反應(yīng)的潛能[36]。這為ZIKV感染通過引發(fā)感染者的自身免疫性反應(yīng)從而損傷大腦發(fā)育提供了有力支持，也為進(jìn)一步探索ZIKV與小頭癥的關(guān)系提供了新思路。

3 ZIKV預(yù)防疫苗研究：任重道遠(yuǎn)

2016年初，WHO召集了一次關(guān)于ZIKV的多學(xué)科討論會(huì)，對(duì)加速研究ZIKV預(yù)防性疫苗的緊迫性達(dá)成一致[37]。以黃熱病病毒(yellow fever virus，YFV)、日本腦炎病毒(Japanese encephalitis virus，JEV)及登革病毒(dengue virus，DENV)等黃病毒疫苗的相關(guān)研究為先例[38-40]，研發(fā)針對(duì)ZIKV的保護(hù)性疫苗是可行的。目前，ZIKV相關(guān)疫苗研發(fā)有了很大進(jìn)展，研究者們分別以不同的抗原呈現(xiàn)方式來引發(fā)機(jī)體的保護(hù)性免疫，包括核酸疫苗、純化滅活病毒疫苗(purified inactivated virus，PIV)、減毒活病毒疫苗(live attenuated virus，LAV)及其他能表達(dá)ZIKV抗原的載體疫苗[41]。Larocca等構(gòu)建了prM-Env共表達(dá)質(zhì)?？筞IKV的DNA疫苗，其對(duì)ZIKV感染的抵抗作用在小鼠模型中得到驗(yàn)證[42]。類似的西尼羅病毒(West Nile virus，WNV)和DENV的DNA疫苗已進(jìn)入Ⅰ期臨床試驗(yàn)[43-44]，這鼓舞了ZIKV核酸疫苗的研究。基于DENV安全有效的LAV臨床前試驗(yàn)結(jié)果[45]，針對(duì)ZIKV的LAV也投入研發(fā)。此外，針對(duì)黃病毒的PIV在多種病毒中進(jìn)行了研發(fā)，包括DENV、蜱傳腦炎病毒(tick borne encephalitis virus，TBEV)和JEV[46-48]?？傊?，PIV具有很廣泛的應(yīng)用價(jià)值，包括較廣的接種年齡范圍、適用于抵抗力低下的免疫缺陷者及可與其他疫苗共用，其安全性也被普遍認(rèn)可。因此，ZIKV疫苗研發(fā)可充分利用PIV的這些優(yōu)點(diǎn)。關(guān)于ZIKV疫苗的研究進(jìn)展見表1。其中，Kim等研發(fā)了針對(duì)E蛋白胞外區(qū)的特異性腺病毒載體疫苗，并在乳鼠模型中獲得驗(yàn)證。乳鼠由接種疫苗的雌鼠與未接種疫苗的雄鼠交配所得，顯示了其潛在應(yīng)用價(jià)值，能有效避免因女性孕前感染ZIKV而導(dǎo)致胎兒小頭畸形的風(fēng)險(xiǎn)[49-50]。這些不同種類的ZIKV疫苗均通過動(dòng)物模型驗(yàn)證了其高效的體內(nèi)預(yù)防作用，應(yīng)進(jìn)一步進(jìn)行臨床試驗(yàn)，以加快預(yù)防性疫苗的實(shí)際應(yīng)用。

表1 ZIKV疫苗研究進(jìn)展

Tab. 1 The research advances on preventive vaccines for Zika virus

疫苗種類免疫原區(qū)域動(dòng)物模型保護(hù)率DNA疫苗PrM-EnvBalb/c小鼠(6～8周)100%[39]恒河猴100%[46]純化滅活病毒疫苗(PIV)滅活病毒顆粒Balb/c小鼠(6～8周)100%恒河猴100%腺病毒載體重組疫苗PrM-Env恒河猴100%E蛋白胞外區(qū)乳鼠(7d)100%[47]

與DENV類似，ZIKV感染者體內(nèi)會(huì)出現(xiàn)抗體依賴性增強(qiáng)(antibody-dependent enhancement，ADE)現(xiàn)象[51-53]，這為ZIKV預(yù)防性疫苗的安全應(yīng)用增加了難度，需更充足的時(shí)間和更謹(jǐn)慎的安全性評(píng)估[54]。同時(shí)，還要加強(qiáng)對(duì)ZIKV結(jié)構(gòu)蛋白的研究，讓其具有免疫原性的抗原表位成為設(shè)計(jì)抗病毒免疫策略的根本依據(jù)[55-56]。有報(bào)道發(fā)現(xiàn)ZIKV能通過性接觸方式傳播[57]，也有關(guān)于ZIKV可穿過胎盤屏障的研究[58]。ZIKV的這些特點(diǎn)提示疫苗研發(fā)還需重點(diǎn)關(guān)注接種時(shí)期，在性成熟前的青少年時(shí)期接種可在多個(gè)層次更好地阻斷ZIKV播散及消除其帶來的危害，具有更多的實(shí)際應(yīng)用價(jià)值。

預(yù)防性疫苗是戰(zhàn)勝流行性傳染病的最有效方法，隨著對(duì)ZIKV抗原結(jié)構(gòu)及其相關(guān)免疫機(jī)制的認(rèn)識(shí)越來越深入，通過不斷推動(dòng)ZIKV相關(guān)疫苗研發(fā)，預(yù)防性疫苗的成功應(yīng)用指日可待。

4 ZIKV治療藥物研究：形勢(shì)緊迫

目前還沒有針對(duì)ZIKV感染的特異性治療藥物上市。對(duì)ZIKV感染患者，主要進(jìn)行基礎(chǔ)對(duì)癥治療，包括休息、使用退熱藥和鎮(zhèn)痛藥等[59]。隨著ZIKV感染所致并發(fā)癥的發(fā)現(xiàn)越來越多，其治療藥物的需求越來越緊迫。早在全球關(guān)注ZIKV流行之初，美國(guó)Ekins及其同事就呼吁進(jìn)行抗ZIKV感染的藥物研發(fā)工作[60]。為加快這項(xiàng)工作的進(jìn)展，美國(guó)科學(xué)家發(fā)起了OpenZika項(xiàng)目，旨在發(fā)現(xiàn)能結(jié)合ZIKV蛋白晶體結(jié)構(gòu)的具有藥物潛能的化合物，并在全球范圍內(nèi)共享[61]。2016年10月， Xu等對(duì)約6 000種已批準(zhǔn)或還處于臨床試驗(yàn)階段的藥物和有藥理活性的小分子化合物進(jìn)行了高通量篩選[62]。結(jié)果顯示，恩利卡生(Emricasan)作為天冬氨酸特異性半胱氨酸蛋白酶(cysteinyl aspartate specific protease，caspase)廣譜抑制劑，能有效保護(hù)大腦皮質(zhì)神經(jīng)祖細(xì)胞抵抗ZIKV感染；B類驅(qū)蟲劑氯硝柳胺和其他10種細(xì)胞周期蛋白依賴性激酶(cyclin-dependent kinase，CDK)抑制劑均能抑制ZIKV復(fù)制。此外，他們還發(fā)現(xiàn)神經(jīng)保護(hù)性復(fù)合物與抗病毒藥物聯(lián)用能進(jìn)一步增強(qiáng)對(duì)神經(jīng)祖細(xì)胞和星形膠質(zhì)細(xì)胞的保護(hù)，避免其發(fā)生ZIKV誘導(dǎo)的細(xì)胞死亡。類似Xu等進(jìn)行的小分子藥物高通量篩選能快速發(fā)現(xiàn)ZIKV潛在治療藥物，且成本較低，容易實(shí)現(xiàn)。但小分子藥物存在較大的安全性風(fēng)險(xiǎn)，尤其是對(duì)孕婦群體。目前，在多角度、全方位證據(jù)指向孕婦感染ZIKV會(huì)導(dǎo)致胎兒小頭畸形甚至流產(chǎn)等不良后果的情況下，孕婦感染者的治療藥物需求尤為迫切，ZIKV的治療藥物研發(fā)應(yīng)重視在孕婦和備孕者等特殊群體中的應(yīng)用[63-64]。當(dāng)然，如果能直接對(duì)美國(guó)食品藥品管理局(Food and Drug Administration，F(xiàn)DA)已批準(zhǔn)的孕婦用藥進(jìn)行抗ZIKV療效篩選可保證孕婦群體的安全性，篩選結(jié)果的可行性也能得到保障。

干擾素誘導(dǎo)的跨膜蛋白(interferon-induced transmembrane protein，IFITM)具有廣泛的抗病毒作用，對(duì)與ZIKV相近的WNV和DENV均有抑制作用[65-67]。美國(guó)Savidis等據(jù)此研究了IFITM對(duì)ZIKV的影響，發(fā)現(xiàn)IFITM1和IFITM3均能在早期階段抑制ZIKV復(fù)制，為研發(fā)IFITM生物制劑治療ZIKV感染提供了思路[68]。

針對(duì)ZIKV治療，各國(guó)科學(xué)家也在積極探索安全性較高的抗體蛋白藥物。黃病毒E蛋白在病毒進(jìn)入宿主細(xì)胞過程中發(fā)揮關(guān)鍵作用，成為中和性抗體藥物的重要靶點(diǎn)。美國(guó)Sapparapu等[69]從有ZIKV感染史的人體中分離出能抑制非洲、亞洲和美洲3類ZIKV毒株活性的人類中和性抗體ZIKV-117，抗原表位作圖揭示其可識(shí)別E蛋白二聚體連接處表位進(jìn)而中和ZIKV。他們還通過小鼠模型證實(shí)了ZIKV-117對(duì)ZIKV感染的體內(nèi)治療效應(yīng)并能保護(hù)孕鼠，降低孕鼠胎盤及胎鼠的ZIKV感染。Stettler等[52]發(fā)現(xiàn)了針對(duì)ZIKV E蛋白DⅢ(domain Ⅲ)抗原表位的單克隆抗體ZKA64，對(duì)A129小鼠感染ZIKV有較好的治療效果，不管是感染前或感染后1 d應(yīng)用均能有效避免ZIKV所致體重減輕及死亡，與Zhao等[70]認(rèn)為的應(yīng)將ZIKV E蛋白DⅢ作為中和性抗體藥物研發(fā)關(guān)鍵表位的觀點(diǎn)一致。C10是另一具有ZIKV交叉中和活性的抗DENV人類中和性抗體，可能通過阻止融合過程中E蛋白發(fā)生結(jié)構(gòu)重組而抑制ZIKV，也是ZIKV感染的潛在抗體治療藥物[71]。此外，黃病毒E蛋白還包含一個(gè)疏水性的融合環(huán)(fusion loop)片段，介導(dǎo)病毒與宿主細(xì)胞融合，這段序列在黃病毒屬中高度保守?；谶@段保守序列，Deng等研發(fā)了單克隆抗體2A10G6，對(duì)DENV、YFV和ZIKV均有較好的中和效果，空斑減少中和試驗(yàn)(plaque reduction neutralization test，PRNT)顯示，2A10G6對(duì)ZIKV的50%中和效價(jià)為249 μg/mL[72-73]。2A10G6也有希望成為抗黃病毒屬的廣譜治療性抗體藥物。Z23和Z3L1是來源于ZIKV感染者的人類中和性抗體，研究發(fā)現(xiàn)它們分別通過與E蛋白DⅠ、DⅡ和DⅢ表位結(jié)合發(fā)揮中和作用，體內(nèi)外實(shí)驗(yàn)證實(shí)這兩種抗體對(duì)ZIKV均有很好的中和效果[74]。一部分抗體蛋白藥物在小鼠模型中顯示了高效的治療作用，但需在此基礎(chǔ)上建立靈長(zhǎng)類動(dòng)物模型并進(jìn)行驗(yàn)證。ZIKV的抗體蛋白藥物有高效治療作用，但潛在的ADE及不可忽視的高成本可能會(huì)限制其廣泛應(yīng)用，尤其是在發(fā)展中國(guó)家。抗體無法穿過睪血屏障，曾有報(bào)道顯示埃博拉病毒(Ebola virus，EBOV)感染者使用抗體治愈出院后仍以性接觸方式傳播，將EBOV傳給其性伴侶[75]。最近，Nature及Cell發(fā)表的兩項(xiàng)研究均顯示ZIKV感染會(huì)引發(fā)睪丸損傷，最終導(dǎo)致雄性不育[76-77]。因此，抗體藥物可能無法清除睪丸內(nèi)的ZIKV及遏制睪丸損傷，從而無法有效阻斷ZIKV的性接觸傳播。除抗體外，多肽藥物也屬于蛋白藥物，具有較好的安全性，且相對(duì)抗體而言成本更低，適合發(fā)展中國(guó)家。同時(shí)，多肽藥物能穿過胎盤及睪血屏障，可應(yīng)用于孕期胎兒及男性睪丸內(nèi)病毒的清除，用途更加廣泛，在預(yù)防ZIKV性傳播中具有更顯著的優(yōu)勢(shì)。

中藥制劑在治療ZIKV感染中也取得了滿意效果。我國(guó)首例輸入性ZIKV感染病例于2016年2月6日入住贛縣人民醫(yī)院感染疾病科，該院對(duì)患者主要采用中藥制劑喜炎平注射液進(jìn)行抗病毒治療，以及布洛芬、氯霉素滴眼液等對(duì)癥治療，患者于2月14日痊愈出院[78]。這充分表明中西醫(yī)結(jié)合治療ZIKV感染具有一定的優(yōu)勢(shì)。

自ZIKV發(fā)現(xiàn)到近年暴發(fā)流行，間隔幾十年的研究空白導(dǎo)致人們面對(duì)其引發(fā)的公共衛(wèi)生事件時(shí)措手不及。應(yīng)謹(jǐn)記，后代的健康將取決于我們今天的選擇，針對(duì)ZIKV防治相關(guān)研究的腳步不能停止。

5 結(jié)語

隨著ZIKV持續(xù)傳播流行，縱觀既往美洲地區(qū)DENV流行經(jīng)驗(yàn)及近期ZIKV傳播趨勢(shì)，ZIKV可能還會(huì)在越來越多的地區(qū)發(fā)生流行，甚至達(dá)到全球范圍[79]。2015年迄今，ZIKV的相關(guān)研究在多方面取得了重大成果，包括ZIKV基因序列測(cè)定和蛋白結(jié)構(gòu)分析、建立能協(xié)助研究ZIKV是否引發(fā)小頭癥及其機(jī)制的體內(nèi)外模型、研發(fā)針對(duì)ZIKV的預(yù)防性疫苗及發(fā)現(xiàn)或發(fā)明抗ZIKV感染的藥物或化合物。近兩年，盡管ZIKV的相關(guān)研究進(jìn)展越來越多，但其防治藥物的臨床應(yīng)用尚未實(shí)現(xiàn)，特別是針對(duì)孕婦群體。ZIKV屬于眾多黃病毒中的一員，其近期暴發(fā)流行的影響相比于整個(gè)黃病毒屬曾帶來的傷害仍是冰山一角。為了能更好地應(yīng)對(duì)類似ZIKV或DENV的其他黃病毒流行，科學(xué)家們應(yīng)投入研究抗黃病毒的廣譜性防治藥物。目前，流行地區(qū)急需針對(duì)ZIKV的防治措施。相信通過各國(guó)研究者的全力合作，一定能成功遏制此次ZIKV流行。

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. LU Lu, E-mail: lul@fudan.edu.cn

Zika virus causes microcephaly? Prophylaxis and treatment are more urgent as the causal relationship is sure

WANG Xiaohuan1,2, ZOU Peng1, LI Yuan1, LU Lu1,2

1.ShanghaiPublicHealthClinicalCenterAffiliatedtoFudanUniversity,Shanghai201508,China; 2.KeyLaboratoryofMedicalMolecularVirology,MinistriesofEducationandHealth,SchoolofBasicMedicalSciences,FudanUniversity,Shanghai200032,China

Since early 2015, Zika virus has caused severe epidemic outbreaks, which started from Brazil involving dozens of regions and countries successively, and contemporaneously growing infants with microcephaly have made the whole global alert against Zika virus. A variety of potential neurological disorders caused by Zika virus infection are under exploring worldwide. The need of treatments for infectors is more and more urgent because of increasing evidences indicating that Zika virus is able to impair the brain development of the embryo in cellular level and animal model. This review will summarize recent research achievements concerning epidemiology and advances among causal relationship with microcephaly, potential preventive vaccines and therapeutic drugs of Zika virus.

Zika virus; Microcephaly; Epidemiology; Preventive vaccine; Therapeutic drug

上海市公共衛(wèi)生臨床中心院級(jí)科研課題(2016-27)

陸路

2016-12-23)