Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality.
Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality.
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感染弓形虫的亨廷顿疾病小鼠表现出早期的Kynurenine途径激活，CD8+ T细胞反应改变和过早死亡。
DOI：
10.1371/journal.pone.0162404
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gigley JP
中科院分区：
文献类型：
--
作者：
Donley DW;Olson AR;Raisbeck MF;Fox JH;Gigley JP
亨廷顿病（HD）是由亨廷顿蛋白中的多聚谷氨酰胺重复扩增引起的进行性神经退行性疾病。色氨酸降解的犬尿氨酸途径的激活与HD的发病机制有关。吲哚胺-2，3-双加氧酶（IDO）催化色氨酸氧化为犬尿氨酸，这是该途径的第一步。流行的神经侵入性原虫病原体弓形虫（T。弓形虫）导致免疫活性个体的临床上无症状的终身感染。T.弓形虫感染导致IDO的激活，IDO通过消耗寄生虫不能合成的色氨酸而提供一些对抗寄生虫的保护。因此，犬尿氨酸途径可能代表HD和T之间的协同作用点。弓形虫感染我们在此表明，在对应于早期晚期HD的14周时，未感染N171- 82 Q HD小鼠的额叶皮质和纹状体中IDO活性升高至少四倍。T.弓形虫感染5周导致HD小鼠皮质IDO活性升高。HD感染的小鼠比野生型感染的小鼠和HD对照小鼠显著更早死亡。在死亡之前，与野生型感染的小鼠相比，感染的HD小鼠表现出脑和脾中的CD 8 + T淋巴细胞增殖降低。我们首次证明HD小鼠对感染因子的反应改变，其特征在于过早死亡、免疫反应改变和IDO的早期激活。研究结果有助于理解T.弓形虫感染可能与介导HD神经变性的途径相互作用。
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.
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影响因子：
3.1
作者：
GUPTA, SL;CARLIN, JM;MURPHY, MJ
通讯作者：
MURPHY, MJ
影响因子：
3.7
作者：
Miller JR;Träger U;Andre R;Tabrizi SJ
通讯作者：
Tabrizi SJ
影响因子：
5
作者：
Jones, JL;Kruszon-Moran, D;McAuley, JB
通讯作者：
McAuley, JB
DOI：
10.1093/brain/awv384
发表时间：
2016-03
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Boussicault L;Alves S;Lamazière A;Planques A;Heck N;Moumné L;Despres G;Bolte S;Hu A;Pagès C;Galvan L;Piguet F;Aubourg P;Cartier N;Caboche J;Betuing S
通讯作者：
Betuing S
影响因子：
2.6
作者：
Carter CJ
通讯作者：
Carter CJ