Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase
Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase
复制标题
DOI：
10.1038/s41598-020-61483-4
复制
发表时间：
2020-03-12
影响因子：
4.6
通讯作者：
Mabbott, Neil A.
中科院分区：
文献类型：
--
作者：
Donaldson, David S.;Bradford, Barry M.;Mabbott, Neil A.
中枢神经系统（CNS）的朊病毒感染可导致广泛的神经变性。全身炎症会影响某些神经退行性疾病的进展。因此，我们使用胃肠道蠕虫病原体鼠鞭虫来检验胃肠道感染的慢性全身炎症反应同样会影响中枢神经系统朊病毒病发病机制的假设。将朊病毒直接注射到小鼠的中枢神经系统中，然后在临床症状出现之前口服鼠毛虫进行共同感染。我们发现，低剂量的鼠毛虫的共同感染会导致慢性 T 辅助细胞 1 型极化全身免疫反应的发展，从而加速临床朊病毒病的发作。相比之下，同时感染高剂量的鼠毛虫会诱导辅助性 T 细胞 2 型极化免疫反应，但不会影响朊病毒病的发病机制。中枢神经系统朊病毒感染后第 105 天，同时感染低剂量鼠毛虫的小鼠存活时间缩短，这与临床前阶段大脑中星形胶质细胞活化增强相一致。这些数据有助于我们了解全身炎症如何加剧中枢神经系统神经退行性病变的进展。
Prion infections in the central nervous system (CNS) can cause extensive neurodegeneration. Systemic inflammation can affect the progression of some neurodegenerative disorders. Therefore, we used the gastrointestinal helminth pathogen Trichuris muris to test the hypothesis that a chronic systemic inflammatory response to a gastrointestinal infection would similarly affect CNS prion disease pathogenesis. Mice were injected with prions directly into the CNS and subsequently orally co-infected with T. muris before the onset of clinical signs. We show that co-infection with a low dose of T. muris that leads to the development of a chronic T helper cell type 1-polarized systemic immune response accelerated the onset of clinical prion disease. In contrast, co-infection with a high dose of T. muris that induces a T helper cell type 2-polarized immune response did not affect prion disease pathogenesis. The reduced survival times in mice co-infected with a low dose of T. muris on d 105 after CNS prion infection coincided with enhanced astrocyte activation in the brain during the preclinical phase. These data aid our understanding of how systemic inflammation may augment the progression of neurodegeneration in the CNS.