病毒穿越血腦屏障的兩種方式與可能機(jī)制

朱耐偉，朱勇喆，戚中田

第二軍醫(yī)大學(xué)微生物學(xué)教研室，上海市醫(yī)學(xué)生物防護(hù)重點(diǎn)實(shí)驗(yàn)室， 上海 200433

·綜述·

病毒穿越血腦屏障的兩種方式與可能機(jī)制

朱耐偉，朱勇喆，戚中田

第二軍醫(yī)大學(xué)微生物學(xué)教研室，上海市醫(yī)學(xué)生物防護(hù)重點(diǎn)實(shí)驗(yàn)室， 上海 200433

血腦屏障是維持中樞神經(jīng)系統(tǒng)內(nèi)環(huán)境穩(wěn)定的重要結(jié)構(gòu)，限制血液中大多數(shù)病原體的入侵；但有些病毒可穿越血腦屏障入侵中樞神經(jīng)系統(tǒng)，導(dǎo)致神經(jīng)功能障礙及炎癥性疾病。目前認(rèn)為，病毒可通過細(xì)胞和細(xì)胞間隙兩種方式穿越血腦屏障，前者為直接感染腦微血管內(nèi)皮細(xì)胞和跨細(xì)胞途徑，后者為破壞內(nèi)皮細(xì)胞間緊密連接及“特洛伊木馬”途徑。本文就近年來病毒穿越血腦屏障的途徑和機(jī)制進(jìn)行綜述。

病毒；血腦屏障；機(jī)制

血腦屏障(blood-brain barrier，BBB)介于血液與腦組織之間，是維持中樞神經(jīng)系統(tǒng)內(nèi)環(huán)境穩(wěn)定的重要組織結(jié)構(gòu)，為抵御病原體入侵的天然屏障。然而，有些病毒可通過不同的途徑和機(jī)制穿越血腦屏障入侵腦部，破壞神經(jīng)細(xì)胞與腦內(nèi)微環(huán)境，引起中樞神經(jīng)系統(tǒng)感染。這些病毒包括人類免疫缺陷病毒(human immunodeficiency virus，HIV)、麻疹病毒(measles virus)、脊髓灰質(zhì)炎病毒(poliovirus，PV)、乙型腦炎病毒(Japanese encephalitis virus，JEV)和西尼羅病毒(West Nile virus，WNV)[1]，是全球腦炎發(fā)病和致死的重要原因之一[2]。本文就近年來病毒穿越血腦屏障的方式和機(jī)制進(jìn)行綜述。

1 血腦屏障的結(jié)構(gòu)特點(diǎn)

1885年，Enrlich等[3]發(fā)現(xiàn)染料并不能經(jīng)靜脈注射進(jìn)入中樞神經(jīng)系統(tǒng)。1909年，Goldmann等[3]認(rèn)為腦內(nèi)存在一種結(jié)構(gòu)性屏障。直到20世紀(jì)中期，Reese和Karnovsky[4]在電鏡下發(fā)現(xiàn)了血腦屏障的超微結(jié)構(gòu)特征：由腦微血管內(nèi)皮細(xì)胞(brain microvascular endothelial cell，BMEC)及其細(xì)胞間的緊密連接(tight junction)、完整的基膜(basement membrane)、周細(xì)胞(pericyte)、小膠質(zhì)細(xì)胞(microglial cell)及星形膠質(zhì)細(xì)胞腳板(astrocytic endfeet)圍成的神經(jīng)膠質(zhì)膜構(gòu)成[3-4](圖1)。其中BMEC是血腦屏障的主要結(jié)構(gòu)，其頂端面與腦微血管中的血流接觸，基底面則與腦內(nèi)相通，BMEC間的緊密連接分子限制細(xì)胞旁路途徑的物質(zhì)轉(zhuǎn)運(yùn)。此外，周細(xì)胞調(diào)控血管形成及血管的完整性；小膠質(zhì)細(xì)胞在病原體刺激下可釋放細(xì)胞因子，清除病原體；星形膠質(zhì)細(xì)胞可分泌可溶性因子促進(jìn)緊密連接和屏障的完整性[5-7]。這些結(jié)構(gòu)使病毒不能隨意侵入中樞神經(jīng)系統(tǒng)，引起腦內(nèi)感染。

圖1 血腦屏障的結(jié)構(gòu)特點(diǎn)

Fig.1 Structural characteristics of the blood-brain barrier

2 病毒穿越血腦屏障的途徑

病毒穿越血腦屏障是中樞神經(jīng)系統(tǒng)感染發(fā)生的前提。當(dāng)病毒穿過血腦屏障后，病毒表面蛋白與腦內(nèi)細(xì)胞表面蛋白或受體相互作用，通過炎癥因子和病毒自身蛋白導(dǎo)致神經(jīng)細(xì)胞變性壞死，引起意識障礙、驚厥等腦炎癥狀[8]。血腦屏障作為天然固有屏障，極大限制了各種病原體入腦的概率[9]。目前認(rèn)為病毒可通過以下兩種方式穿越血腦屏障。

2.1 病毒通過細(xì)胞穿越血腦屏障

2.1.1 直接感染BMEC BMEC是血腦屏障的主要結(jié)構(gòu)，感染BMEC是病毒進(jìn)入中樞神經(jīng)系統(tǒng)的必經(jīng)之路之一(圖2A)；小膠質(zhì)細(xì)胞與神經(jīng)膠質(zhì)細(xì)胞作為血腦屏障的組成，病毒也可通過感染這些細(xì)胞進(jìn)入中樞神經(jīng)系統(tǒng)。Chapagain等[10]發(fā)現(xiàn)人多瘤病毒JC(human polyomavirus JC，JCV)可感染人腦微血管內(nèi)皮細(xì)胞(human brain microvascular endothelial cell，HBMEC)，感染3 d后可在胞內(nèi)檢測到病毒載量；而感染10 d后則可通過激光共聚焦顯微鏡觀察到HBMEC表達(dá)JCV早期蛋白標(biāo)記T抗原。釋放的子代病毒具有感染性并可在敏感細(xì)胞系中有效復(fù)制，因此推測JCV在體內(nèi)可通過感染HBMEC來穿越血腦屏障，進(jìn)一步感染神經(jīng)細(xì)胞，引起進(jìn)行性多灶性白質(zhì)腦病。Afonso等[11]發(fā)現(xiàn)人嗜T細(xì)胞病毒1型(human T lymphotropic virus type 1，HTLV-1)可在HBMEC內(nèi)復(fù)制并釋放子代病毒，提示內(nèi)皮細(xì)胞感染可能使子代病毒進(jìn)入中樞神經(jīng)系統(tǒng)，造成神經(jīng)元變性與壞死，引起HTLV-1相關(guān)脊髓病和熱帶痙攣性癱瘓病。

Coyne等[12]發(fā)現(xiàn)PV可通過結(jié)合PV受體，繼而激活酪氨酸激酶和RhoA GTP酶，經(jīng)內(nèi)吞方式侵入HBMEC后復(fù)制增殖，提示血源性病毒可能通過感染HBMEC來穿越血腦屏障從而進(jìn)入中樞神經(jīng)系統(tǒng)。

Casiraghi等[13]發(fā)現(xiàn)EB病毒(Epstein-Barr virus, EBV)可感染HBMEC，使細(xì)胞因子及趨化因子升高，從而誘導(dǎo)血腦屏障破壞，導(dǎo)致自身反應(yīng)性淋巴細(xì)胞入腦，損傷神經(jīng)元，引起多發(fā)性硬化癥。

Lai等[14]發(fā)現(xiàn)HBMEC對JEV易感，在細(xì)胞內(nèi)僅能少量復(fù)制，但不會引起細(xì)胞死亡和破壞屏障的完整性。Verma等[15]發(fā)現(xiàn)WNV可感染HBMEC并在其內(nèi)復(fù)制，但未觀察到細(xì)胞死亡。

Mankowski等[16]通過對猴免疫缺陷病毒(simian immunodeficiency virus，SIV)感染的猴腦組織進(jìn)行免疫組化分析，在血管內(nèi)皮處檢測到病毒RNA，并通過電鏡在內(nèi)皮細(xì)胞中觀察到病毒顆粒，提示SIV可感染BMEC并穿越血腦屏障。HIV的多種病毒蛋白可與HBMEC相互作用，從而實(shí)現(xiàn)對血腦屏障完整性的破壞[17]。例如，包膜蛋白gp120在血管內(nèi)皮細(xì)胞處可增強(qiáng)脂質(zhì)的過氧化作用，上調(diào)白細(xì)胞介素1β(interleukin 1β，IL-1β)和誘導(dǎo)型一氧化氮合酶(inducible nitric oxide synthase，iNOS)，從而破壞血腦屏障[18]。病毒反式激活因子(trans-activating factor, Tat)含有使其順利通過血腦屏障的跨膜結(jié)構(gòu)域[19]，且可通過CD40配體依賴途徑增加血腦屏障滲透性[20]；Tat還可破壞血腦屏障處的周細(xì)胞，破壞血腦屏障的完整性[21]。負(fù)調(diào)節(jié)因子(negative regulatory factor, Nef)則可通過促凋亡基因如含半胱氨酸的天冬氨酸蛋白水解酶6(cysteinyl aspartate specific proteinase 6，caspase-6)、caspase-8、caspase-9及caspase-10，誘導(dǎo)HBMEC凋亡，以改變血腦屏障的完整性，有利于HIV入侵中樞神經(jīng)系統(tǒng)[18]。

2.1.2 跨細(xì)胞途徑 血腦屏障在正常情況下是非滲透性的，但其存在多種特殊的跨細(xì)胞轉(zhuǎn)運(yùn)機(jī)制[22]，如內(nèi)吞與轉(zhuǎn)胞吞機(jī)制，為病毒入侵中樞神經(jīng)系統(tǒng)提供了可能途徑(圖2B)。HTLV-1顆?？山?jīng)內(nèi)吞作用進(jìn)入內(nèi)皮細(xì)胞，并從基底面釋放出來[23]；HIV可通過BMEC的巨胞飲作用跨越血腦屏障[24-25]；JEV可通過胞內(nèi)囊泡在腦內(nèi)皮細(xì)胞和周細(xì)胞中進(jìn)行轉(zhuǎn)運(yùn)[26]；而WNV的病毒樣顆粒(virus-like particle，VLP)則可從內(nèi)皮細(xì)胞的頂端轉(zhuǎn)移到基底部[27]，Verma等[15]應(yīng)用體外血腦屏障模型(由體外培養(yǎng)的單層HBMEC構(gòu)成)，發(fā)現(xiàn)WNV在不破壞血腦屏障完整性的前提下可穿越血腦屏障，提示其可能通過跨細(xì)胞途徑侵入中樞神經(jīng)系統(tǒng)。然而，上述結(jié)果均來自體外實(shí)驗(yàn)，而BMEC在體內(nèi)與體外環(huán)境中有明顯區(qū)別，該機(jī)制仍需體內(nèi)實(shí)驗(yàn)來證實(shí)。

2.2 病毒通過細(xì)胞間隙穿越血腦屏障

2.2.1 破壞內(nèi)皮細(xì)胞間緊密連接 BMEC間的緊密連接是血腦屏障完整性的結(jié)構(gòu)與功能基礎(chǔ)，其調(diào)控物質(zhì)及限制病原體通過細(xì)胞旁路途徑進(jìn)入中樞神經(jīng)系統(tǒng)[28]。緊密連接由多種跨膜蛋白組成，如閉合蛋白(occludin)、封閉蛋白(claudin)及連接黏附分子等，這些跨膜蛋白又通過緊密連接分子(zonula occluden 1，ZO-1)等蛋白復(fù)合體固定在內(nèi)皮細(xì)胞上[29-30]。某些病毒感染時可導(dǎo)致緊密連接破壞，血腦屏障通透性增加，病毒穿越血腦屏障引起中樞神經(jīng)系統(tǒng)感染(圖2C)。

鼠腺病毒1型(mouse adenovirus type 1，MAV-1)感染HBMEC可引起明顯的組織病理學(xué)變化，增加血腦屏障通透性。雖然MAV-1感染會引起小鼠腦組織炎性細(xì)胞浸潤，但其對血腦屏障的破壞并不依賴炎癥反應(yīng)，因?yàn)檠装Y反應(yīng)減輕后血腦屏障的破壞程度并未降低[31-32]。Gralinski等[33]認(rèn)為，MAV-1感染HBMEC后可能激發(fā)了宿主的天然免疫反應(yīng)，并通過基質(zhì)金屬蛋白酶(matrix metalloproteinase，MMP)降解了緊密連接蛋白，導(dǎo)致細(xì)胞緊密連接處的occludin及claudin-5降低，增加了血腦屏障的滲透性。

Chang等[34]發(fā)現(xiàn)JEV感染星形膠質(zhì)細(xì)胞后可引起血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)、IL-6及MMP-2和MMP-9釋放，通過內(nèi)皮細(xì)胞的Jak2/STAT3信號途徑及泛素蛋白酶體導(dǎo)致ZO-1和claudin-5降解，提示星形膠質(zhì)細(xì)胞的感染可能破壞了血腦屏障的完整性。

WNV直接感染HBMEC并不會引起細(xì)胞間緊密連接蛋白發(fā)生變化[15]；但將感染W(wǎng)NV的星形膠質(zhì)細(xì)胞上清液加入體外血腦屏障模型中，可引起HBMEC間緊密連接蛋白降解，從而破壞血腦屏障的完整性[35]。進(jìn)一步的分子機(jī)制研究發(fā)現(xiàn)，WNV感染后，星形膠質(zhì)細(xì)胞分泌的MMP-1和MMP-3可直接消化緊密連接蛋白，或通過激活MMP-9對緊密連接蛋白造成破壞，使WNV更易進(jìn)入腦部，感染中樞神經(jīng)系統(tǒng)[35-36]。

HTLV-1可誘導(dǎo)ZO-1的重排，改變緊密連接的分布。進(jìn)一步研究發(fā)現(xiàn)，HTLV-1的蛋白Tax可與ZO-1的PDZ結(jié)構(gòu)域(PZD95、Discs-large、ZO-1三者結(jié)構(gòu)域的簡稱)相互作用[37-38]。此外，HTLV-1感染的淋巴細(xì)胞還可通過釋放IL-1α和腫瘤壞死因子α(tumor necrosis factor α，TNF-α)改變緊密連接的結(jié)構(gòu)，以增加細(xì)胞旁路的通透性，使病毒穿越血腦屏障[39-40]。

A: Direct infection of the brain microvascular endothelial cells. B: Transcellular pathway. C: Breaching of the tight junction between endothelial cells. D: The “Trojan horse” pathway.

圖2 病毒穿越血腦屏障的途徑

Fig.2 Pathways of virus crossing the blood-brain barrier

在體外血腦屏障模型中，感染HIV的單核細(xì)胞可引起MMP-2和MMP-9增加，以及ZO-1、occludin、claudin-5下降，導(dǎo)致血腦屏障滲透性增加。Dallasta等[41]也觀察到類似現(xiàn)象，HIV腦炎患者的皮質(zhì)下白質(zhì)區(qū)、灰質(zhì)區(qū)及基底節(jié)均有ZO-1蛋白的缺失。此外，HIV蛋白可通過多種途徑影響緊密連接，如包膜蛋白gp120可通過酪氨酸磷酸化激活局部黏著斑激酶(focal adhesion kinase，F(xiàn)AK)途徑，從而下調(diào)ZO-1、ZO-2及occludin等[42-43]；同時gp120可增加MMP-2和MMP-9表達(dá)，繼而破壞claudin-5形成[44]。病毒蛋白R(viral protein R，Vpr)則可通過感染星形膠質(zhì)細(xì)胞，分泌趨化因子和炎癥因子來破壞血腦屏障間的緊密連接，增加血腦屏障的滲透性[18]。Tat一方面可激活BMEC的氧化還原通路和轉(zhuǎn)錄因子，并通過刺激蛋白激酶C(protein kinase C，PKC)和Ras/絲裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)途徑破壞細(xì)胞內(nèi)氧化還原反應(yīng)，導(dǎo)致緊密連接蛋白變性和失活[45]；另一方面可通過ras同源基因家族成員A (ras homolog gene family，member A，RhoA)/Rho相關(guān)卷曲螺旋蛋白激酶(Rho-associated coiled-coil containing protein kinase，ROCK)途徑或上調(diào)MMP-9表達(dá)來下調(diào)或降解occludin，從而破壞緊密連接蛋白的完整性[18]。此外，Tat還可引起緊密連接蛋白的磷酸化，破壞緊密連接蛋白復(fù)合體的聚合，增加內(nèi)皮細(xì)胞的滲透性[46]。Raymond等[47]發(fā)現(xiàn)小膠質(zhì)細(xì)胞來源的Nef+外泌體可明顯下調(diào)體外血腦屏障模型中ZO-1的表達(dá)，提示來自小膠質(zhì)細(xì)胞的感染HIV的外泌體可能參與破壞血腦屏障的完整性和滲透性。

血腦屏障處細(xì)胞因子種類與其效應(yīng)之間的平衡是復(fù)雜的。多數(shù)情況下，病毒感染BMEC可增加促炎癥細(xì)胞因子如TNF-α、IL-1β、IL-6、λ干擾素(interferon λ，IFN-λ)等釋放，破壞BMEC間的緊密連接，從而破壞血腦屏障的完整性。星形膠質(zhì)細(xì)胞、周細(xì)胞、BMEC及白細(xì)胞等均可產(chǎn)生上述細(xì)胞因子。不同的細(xì)胞因子其作用機(jī)制各不相同，對血腦屏障的作用也不同。MMP在病毒感染時可直接降解緊密連接，破壞血腦屏障，加速病毒感染中樞神經(jīng)系統(tǒng)[3]；而Ⅰ型干擾素(如IFN-β)和Ⅲ型干擾素(IFN-λ)可穩(wěn)定緊密連接，同時激活BMEC中的TAM(Tyro3、Axl和 Mertk三者的統(tǒng)稱)受體以協(xié)同干擾素的作用，從而增強(qiáng)緊密連接的穩(wěn)定性，維持血腦屏障的完整性[3,48]。

2.2.2 “特洛伊木馬”途徑 病毒可通過“特洛伊木馬”途徑入侵中樞神經(jīng)系統(tǒng)，即攜帶病毒的白細(xì)胞穿越血腦屏障(圖2D)。單核細(xì)胞或巨噬細(xì)胞的感染被認(rèn)為是免疫缺陷病毒穿越血腦屏障的主要機(jī)制，包括SIV和HIV[49-50]。SIV或HIV感染時，大量CD16+單核細(xì)胞在外周擴(kuò)增，該單核細(xì)胞與趨化因子結(jié)合后能促進(jìn)HIV或SIV感染的單核細(xì)胞與BMEC接觸與黏附。Clay等[50]在追蹤熒光素標(biāo)記的單核細(xì)胞時發(fā)現(xiàn)，感染SIV的單核細(xì)胞快速定位于腦血管周圍和脈絡(luò)叢，提示其穿越了中樞神經(jīng)系統(tǒng)屏障。腦內(nèi)和腦脊液內(nèi)檢測到SIV出現(xiàn)的時間與單核細(xì)胞入侵中樞神經(jīng)系統(tǒng)的時間相一致，提示單核細(xì)胞介導(dǎo)了SIV的神經(jīng)感染。Alexaki等[49]證明腦組織中CD16+單核細(xì)胞出現(xiàn)在HIV感染部位，進(jìn)一步研究發(fā)現(xiàn)外周來源的CD16+單核細(xì)胞比其他來源的單核細(xì)胞更易感染HIV。單核細(xì)胞對中樞神經(jīng)系統(tǒng)的入侵可能由血管周圍巨噬細(xì)胞的更替和再分布引起，也可能是CC趨化因子配體2(CC chemokine ligand 2，CCL2)、MMP和促炎癥細(xì)胞因子升高而使血管滲透性增加導(dǎo)致[51-52]。此外，Tat可誘發(fā)內(nèi)皮細(xì)胞上的黏附分子及星形膠質(zhì)細(xì)胞分泌趨化因子，促進(jìn)單核細(xì)胞遷移至中樞神經(jīng)系統(tǒng)[53]。

除免疫缺陷病毒外，JCV也可通過挾持白細(xì)胞加速入侵中樞神經(jīng)系統(tǒng)。JCV在體外模型中可從B細(xì)胞轉(zhuǎn)移到膠質(zhì)細(xì)胞，后者是體內(nèi)感染時的主要靶細(xì)胞；同時，體內(nèi)感染JCV時，在外周血B細(xì)胞中可檢測到JCV[10,54]。但B細(xì)胞是否在體內(nèi)作為“特洛伊木馬”用于病毒的入侵和擴(kuò)散，仍未十分明確。

Garcia-Tapia等[55]在體內(nèi)實(shí)驗(yàn)中發(fā)現(xiàn)，WNV可通過朗格罕斯細(xì)胞從感染部位轉(zhuǎn)移到引流淋巴結(jié)，進(jìn)一步感染單核細(xì)胞和部分CD4+淋巴細(xì)胞。此外，淋巴細(xì)胞趨化因子和單核細(xì)胞趨化因子可將外周單核細(xì)胞聚集到中樞神經(jīng)系統(tǒng)的血管周圍區(qū)域。這些聚集的單核細(xì)胞可產(chǎn)生促炎癥因子，破壞血腦屏障的完整性，導(dǎo)致更多白細(xì)胞進(jìn)入中樞神經(jīng)系統(tǒng)。Dai等[56]和Wang等[57]雖然均在腦內(nèi)檢測到WNV抗原與進(jìn)入中樞神經(jīng)系統(tǒng)的白細(xì)胞共定位，但尚未有證據(jù)表明外周感染W(wǎng)NV的白細(xì)胞可進(jìn)入中樞神經(jīng)系統(tǒng)。

雖然白細(xì)胞可抵御病毒感染，但其也可扮演“特洛伊木馬”將病毒攜帶到機(jī)體其他部位。盡管血腦屏障可精密調(diào)控免疫細(xì)胞進(jìn)入中樞神經(jīng)系統(tǒng)，但病毒仍能在免疫監(jiān)測下利用血源性途徑通過感染的白細(xì)胞入侵中樞神經(jīng)系統(tǒng)。

3 病毒穿越血腦屏障的機(jī)制

病毒穿越血腦屏障的機(jī)制尚未明確，但與病毒結(jié)構(gòu)蛋白和細(xì)胞受體的相互作用、受體介導(dǎo)的病毒內(nèi)吞即病毒-細(xì)胞膜融合等過程相關(guān)[58]。JEV編碼的包膜蛋白E位于病毒顆粒表面，是JEV致病與免疫的主要分子。Luca等[59]通過結(jié)構(gòu)生物學(xué)方法解析E蛋白的晶體結(jié)構(gòu)，發(fā)現(xiàn)包膜蛋白含有3個結(jié)構(gòu)域，其中結(jié)構(gòu)域Ⅱ介導(dǎo)JEV與細(xì)胞膜融合，結(jié)構(gòu)域Ⅲ識別細(xì)胞表面的受體，結(jié)構(gòu)域Ⅰ負(fù)責(zé)連接結(jié)構(gòu)域Ⅱ和Ⅲ[60]。Li等[61]發(fā)現(xiàn)結(jié)構(gòu)域Ⅲ中的loop多肽(loop3)可抑制JEV與細(xì)胞的結(jié)合。Yun等[62]將JEV疫苗株SA-14-14-2包膜蛋白的244位甘氨酸替換為谷氨酸后，可使小鼠產(chǎn)生嚴(yán)重的神經(jīng)系統(tǒng)癥狀，提示包膜蛋白對JEV的嗜神經(jīng)性具有重要影響。Liu等[58]發(fā)現(xiàn)包膜蛋白144位組氨酸、258位谷氨酰胺、319位組氨酸和410位蘇氨酸均參與病毒與細(xì)胞膜的融合，為JEV入侵階段的關(guān)鍵位點(diǎn)。Ferguson等[63]發(fā)現(xiàn)塞姆利基森林腦炎病毒(Semliki Forest virus，SFV)包膜蛋白E2中162位和247位氨基酸決定了其穿越血腦屏障的能力。因此，病毒包膜蛋白中某個或某幾個關(guān)鍵氨基酸位點(diǎn)可能介導(dǎo)病毒穿越血腦屏障，但其機(jī)制仍需進(jìn)一步研究。

4 結(jié)語

某些病毒可侵入中樞神經(jīng)系統(tǒng)導(dǎo)致腦炎，而血腦屏障的存在極大限制了病毒入腦引起感染。雖然病毒穿越血腦屏障的機(jī)制尚不十分明確，但目前認(rèn)為病毒可通過直接感染BMEC、破壞內(nèi)皮細(xì)胞間緊密連接、“特洛伊木馬”途徑及跨細(xì)胞途徑穿越血腦屏障。因此，病毒穿越血腦屏障進(jìn)入中樞神經(jīng)系統(tǒng)是多因素、多途徑的過程。仍需通過體內(nèi)和體外實(shí)驗(yàn)，闡明介導(dǎo)病毒穿越血腦屏障的細(xì)胞分子及關(guān)鍵病毒蛋白與氨基酸位點(diǎn)，深入研究穿越血腦屏障過程中病毒自身與細(xì)胞分子間的相互關(guān)系，為恢復(fù)血腦屏障的完整性及阻止病毒入侵中樞神經(jīng)系統(tǒng)提供新的理論依據(jù)和干預(yù)策略。

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. QI Zhongtian, E-mail: qizt@smmu.edu.cn

Two ways and possible mechanisms of virus crossing the blood-brain barrier

ZHU Naiwei, ZHU Yongzhe, QI Zhongtian

DepartmentofMicrobiology,ShanghaiKeyLaboratoryofMedicalBiodefense,TheSecondMilitaryMedicalUniversity,Shanghai200433,China

The blood-brain barrier (BBB) is an important protective structure to maintain the homeostasis of the central nervous system, limiting the invasion of most pathogens in the blood. Some viruses can cross the BBB to invade the central nervous system by cellular and (or) paracellular ways, causing neurological dysfunction. The cellular ways consist of direct infection of the brain microvascular endothelial cells and transcellular pathway. The paracellular ways are composed of breaching of the tight junction between endothelial cells and the “Trojan horse” pathway. In this review, the current research progress on viral impacts on the BBB is summarized.

Virus; Blood-brain barrier; Mechanism

國家自然科學(xué)基金(81273557)

戚中田

2016-09-30)