Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection.
Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection.
复制标题
DOI：
10.3389/fimmu.2021.702048
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Costa VV
中科院分区：
文献类型：
--
作者：
Marim FM;Teixeira DC;Queiroz-Junior CM;Valiate BVS;Alves-Filho JC;Cunha TM;Dantzer R;Teixeira MM;Teixeira AL;Costa VV
寨卡病毒（ZIKV）是一种属于黄病毒科的虫媒病毒，由于其与小头畸形和其他严重神经系统并发症（包括格林-巴利综合征（GBS）和先天性寨卡综合征（CZS））相关，因此成为全球健康威胁。ZIKV疾病与神经炎症和神经元细胞死亡有关。神经退行性过程可由犬尿氨酸途径产生的代谢物加剧，犬尿氨酸途径是色氨酸降解的重要途径，其由于增强的兴奋性毒性而诱导神经元功能障碍。在这里，我们利用了ZIKV诱导的神经变性可以通过阻断犬尿氨酸途径的靶酶吲哚胺2，3-双加氧酶（IDO-1）来挽救的假设。RT-PCR分析显示，从离体感染ZIKV的野生型（WT）小鼠中分离的未分化原代神经元以及感染ZIKV的A129小鼠的大脑中，IDO-1 RNA表达水平增加。在体外和体内系统中，用1-甲基-D-色氨酸（1-MT）对IDO-1酶的药理学抑制导致ZIKV诱导的神经元死亡的显著减少，而不干扰ZIKV在那些细胞中复制的能力。此外，使用经遗传修饰的小鼠（IDO-/-小鼠）和用1-MT处理的A129小鼠的体内分析导致ZIKV感染的A129小鼠的脑中的小神经胶质增生、星形胶质增生和胱天蛋白酶-3阳性细胞减少。有趣的是，在1-MT处理的小鼠的脑中发现CCL 5和CXCL-1趋化因子水平增加。总之，我们的数据表明IDO-1阻断提供了针对ZIKV诱导的神经变性的神经保护作用，并且这适合于通过药理学治疗来抑制。
Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment.
登录
查看更多内容
影响因子：
3.8
作者：
Dowall SD;Graham VA;Rayner E;Atkinson B;Hall G;Watson RJ;Bosworth A;Bonney LC;Kitchen S;Hewson R
通讯作者：
Hewson R
影响因子：
3.8
作者：
Fox, Julie M.;Sage, Leo K.;Tripp, Ralph A.
通讯作者：
Tripp, Ralph A.
影响因子：
4.7
作者：
Doria, Juliana G.;de Souza, Jessica M.;Ribeiro, Fabiola M.
通讯作者：
Ribeiro, Fabiola M.
影响因子：
3.7
作者：
Foureaux G;Franca JR;Nogueira JC;Fulgêncio Gde O;Ribeiro TG;Castilho RO;Yoshida MI;Fuscaldi LL;Fernandes SO;Cardoso VN;Cronemberger S;Faraco AA;Ferreira AJ
通讯作者：
Ferreira AJ
影响因子：
9.3
作者：
Amaral DC;Rachid MA;Vilela MC;Campos RD;Ferreira GP;Rodrigues DH;Lacerda-Queiroz N;Miranda AS;Costa VV;Campos MA;Kroon EG;Teixeira MM;Teixeira AL
通讯作者：
Teixeira AL