Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: Implications for CNS complications.
Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: Implications for CNS complications.
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作者：
一些被证实患有宫内寨卡病毒（ZIKV）感染的儿童出生时无症状，随后表现出神经发育迟缓，表明围产期和产后发育受损。为了对此进行建模，我们用来自2015年巴西爆发的哺乳动物细胞繁殖的ZIKV临床分离株感染出生后（P）5-6天（相当于人类的围产期）易感小鼠。所有感染小鼠在腹膜内接种（dpi）后4天内表现正常，但在5-6 dpi时迅速出现严重的临床体征。在5/6 dpi检查的所有神经组织大体上均正常。然而，在视神经、脑和脊髓中观察到抗ZIKV阳性细胞;主要在白色物质中。与细胞类型特异性标记物的共标记证明少突胶质细胞和星形胶质细胞支持生产性感染。很少观察到ZIKV阳性神经元。在我们详细检查的脊髓白色物质中，凋亡细胞明显;少突胶质细胞的密度显著降低;并且存在局部小胶质细胞反应性，包括NLRP 3炎性体的表达。总之，我们的观察结果表明，临床相关的ZIKV分离株可以直接影响少突胶质细胞。由于原发性少突胶质细胞死亡可导致继发性自身免疫性脱髓鞘，我们的观察结果可能有助于解释出生时无症状婴儿的神经发育延迟，并建议终身监测。在围产期寨卡病毒感染的小鼠模型中，少突胶质细胞是易感的。NLRP 3表达上调。髓鞘缺陷可以解释出生时无症状的先天性感染婴儿的神经发育迟缓。
Some children with proven intrauterine Zika virus (ZIKV) infection who were born asymptomatic subsequently manifested neurodevelopmental delays, pointing to impairment of development perinatally and postnatally. To model this, we infected postnatal day (P) 5–6 (equivalent to the perinatal period in humans) susceptible mice with a mammalian cell‐propagated ZIKV clinical isolate from the Brazilian outbreak in 2015. All infected mice appeared normal up to 4 days post‐intraperitoneal inoculation (dpi), but rapidly developed severe clinical signs at 5–6 dpi. All nervous tissue examined at 5/6 dpi appeared grossly normal. However, anti‐ZIKV positive cells were observed in the optic nerve, brain, and spinal cord; predominantly in white matter. Co‐labeling with cell type specific markers demonstrated oligodendrocytes and astrocytes support productive infection. Rarely, ZIKV positive neurons were observed. In spinal cord white matter, which we examined in detail, apoptotic cells were evident; the density of oligodendrocytes was significantly reduced; and there was localized microglial reactivity including expression of the NLRP3 inflammasome. Together, our observations demonstrate that a clinically relevant ZIKV isolate can directly impact oligodendrocytes. As primary oligodendrocyte cell death can lead later to secondary autoimmune demyelination, our observations may help explain neurodevelopmental delays in infants appearing asymptomatic at birth and commend lifetime surveillance. In a mouse model of perinatal Zika virus infection, oligodendrocytes are susceptible. NLRP3 expression is upregulated. Myelin defects may explain neurodevelopmental delays in congenitally infected infants who were asymptomatic at birth.
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DOI：
10.1056/nejmoa1602412
发表时间：
2016-12-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brasil P;Pereira JP Jr;Moreira ME;Ribeiro Nogueira RM;Damasceno L;Wakimoto M;Rabello RS;Valderramos SG;Halai UA;Salles TS;Zin AA;Horovitz D;Daltro P;Boechat M;Raja Gabaglia C;Carvalho de Sequeira P;Pilotto JH;Medialdea-Carrera R;Cotrim da Cunha D;Abreu de Carvalho LM;Pone M;Machado Siqueira A;Calvet GA;Rodrigues Baião AE;Neves ES;Nassar de Carvalho PR;Hasue RH;Marschik PB;Einspieler C;Janzen C;Cherry JD;Bispo de Filippis AM;Nielsen-Saines K
通讯作者：
Nielsen-Saines K
影响因子：
7.1
作者：
Cumberworth SL;Barrie JA;Cunningham ME;de Figueiredo DPG;Schultz V;Wilder-Smith AJ;Brennan B;Pena LJ;Freitas de Oliveira França R;Linington C;Barnett SC;Willison HJ;Kohl A;Edgar JM
通讯作者：
Edgar JM
影响因子：
158.5
作者：
Driggers, R. W.;Ho, C. -Y.;Vapalahti, O.
通讯作者：
Vapalahti, O.
影响因子：
1.9
作者：
Familiar, Itziar;Boivin, Michael;Ruisenor-Escudero, Horacio
通讯作者：
Ruisenor-Escudero, Horacio
DOI：
10.1097/01.jnen.0000248559.83573.71
发表时间：
2007-03-01
影响因子：
3.2
作者：
Kuhlmann, Tanja;Remington, Leah;Brueck, Wolfgang
通讯作者：
Brueck, Wolfgang