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Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection.
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-03-03 , DOI: 10.1186/s12974-020-01756-x Mazigh Fares 1, 2 , Marielle Cochet-Bernoin 1 , Gaëlle Gonzalez 1 , Claudia N Montero-Menei 3 , Odile Blanchet 4 , Alexandra Benchoua 5 , Claire Boissart 5 , Sylvie Lecollinet 1 , Jennifer Richardson 1 , Nadia Haddad 6 , Muriel Coulpier 1
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-03-03 , DOI: 10.1186/s12974-020-01756-x Mazigh Fares 1, 2 , Marielle Cochet-Bernoin 1 , Gaëlle Gonzalez 1 , Claudia N Montero-Menei 3 , Odile Blanchet 4 , Alexandra Benchoua 5 , Claire Boissart 5 , Sylvie Lecollinet 1 , Jennifer Richardson 1 , Nadia Haddad 6 , Muriel Coulpier 1
Affiliation
BACKGROUND
Tick-borne encephalitis virus (TBEV) is a member of the Flaviviridae family, Flavivirus genus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-Eastern Asia. TBEV tropism is critical for neuropathogenesis, yet little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a new in vitro model of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis.
METHOD
Human neuronal/glial cells were differentiated from neural progenitor cells and infected with the TBEV-Hypr strain. Kinetics of infection, cellular tropism, and cellular responses, including innate immune responses, were characterized by measuring viral genome and viral titer, performing immunofluorescence, enumerating the different cellular types, and determining their rate of infection and by performing PCR array and qRT-PCR. The specific response of neurons and astrocytes was analyzed using the same approaches after enrichment of the neuronal/glial cultures for each cellular subtype.
RESULTS
We showed that infection of human neuronal/glial cells mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death, and astrogliosis. We further showed that these cells conserved their capacity to mount an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures for either neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV.
CONCLUSION
Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They describe a new in vitro model for in-depth study of TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.
中文翻译:
TBEV 感染的病理模型揭示了人类神经元和星形胶质细胞中不同的先天免疫反应,这与它们对感染的易感性相关。
背景技术蜱传脑炎病毒(TBEV)是黄病毒科黄病毒属的成员,该属包括几种重要的人类病原体。它会引起可能导致永久性残疾或死亡的神经系统症状,从医学角度来看,它是中欧/北欧和东北亚的主要虫媒病毒。TBEV 趋向性对于神经发病机制至关重要,但人们对控制人脑细胞对该病毒易感性的分子机制知之甚少。在这项研究中,我们试图建立并表征人脑中 TBEV 感染的新体外模型,并破译细胞类型特异性先天免疫及其与 TBEV 趋向性和神经发病机制的关系。方法 人类神经元/神经胶质细胞由神经祖细胞分化而来,并用 TBEV-Hypr 菌株感染。通过测量病毒基因组和病毒滴度、进行免疫荧光、计数不同的细胞类型并确定其感染率以及进行 PCR 阵列和 qRT-PCR 来表征感染动力学、细胞向性和细胞反应(包括先天免疫反应) 。在对每种细胞亚型的神经元/神经胶质培养物进行富集后,使用相同的方法分析神经元和星形胶质细胞的特异性反应。结果我们发现,人类神经元/神经胶质细胞的感染模仿了人脑中 TBEV 感染的三个主要特征,即优先神经元趋向性、神经元死亡和星形胶质细胞增生。我们进一步表明,这些细胞保留了针对 TBEV 产生抗病毒反应的能力。因此,TBEV 感染的神经元/神经胶质细胞代表了高度相关的病理模型。通过丰富神经元或星形胶质细胞的培养物,我们进一步证明了这两种细胞类型中定性和定量差异的先天免疫反应,这与它们对 TBEV 的特殊易感性相关。结论 因此,我们的结果表明,细胞类型特异性先天免疫可能有助于形成人脑细胞的 TBEV 趋向性。他们描述了一种新的体外模型,用于深入研究 TBEV 诱导的神经发病机制,并提高我们对嗜神经病毒靶向和损伤人脑细胞机制的理解。
更新日期:2020-04-22
中文翻译:
TBEV 感染的病理模型揭示了人类神经元和星形胶质细胞中不同的先天免疫反应,这与它们对感染的易感性相关。
背景技术蜱传脑炎病毒(TBEV)是黄病毒科黄病毒属的成员,该属包括几种重要的人类病原体。它会引起可能导致永久性残疾或死亡的神经系统症状,从医学角度来看,它是中欧/北欧和东北亚的主要虫媒病毒。TBEV 趋向性对于神经发病机制至关重要,但人们对控制人脑细胞对该病毒易感性的分子机制知之甚少。在这项研究中,我们试图建立并表征人脑中 TBEV 感染的新体外模型,并破译细胞类型特异性先天免疫及其与 TBEV 趋向性和神经发病机制的关系。方法 人类神经元/神经胶质细胞由神经祖细胞分化而来,并用 TBEV-Hypr 菌株感染。通过测量病毒基因组和病毒滴度、进行免疫荧光、计数不同的细胞类型并确定其感染率以及进行 PCR 阵列和 qRT-PCR 来表征感染动力学、细胞向性和细胞反应(包括先天免疫反应) 。在对每种细胞亚型的神经元/神经胶质培养物进行富集后,使用相同的方法分析神经元和星形胶质细胞的特异性反应。结果我们发现,人类神经元/神经胶质细胞的感染模仿了人脑中 TBEV 感染的三个主要特征,即优先神经元趋向性、神经元死亡和星形胶质细胞增生。我们进一步表明,这些细胞保留了针对 TBEV 产生抗病毒反应的能力。因此,TBEV 感染的神经元/神经胶质细胞代表了高度相关的病理模型。通过丰富神经元或星形胶质细胞的培养物,我们进一步证明了这两种细胞类型中定性和定量差异的先天免疫反应,这与它们对 TBEV 的特殊易感性相关。结论 因此,我们的结果表明,细胞类型特异性先天免疫可能有助于形成人脑细胞的 TBEV 趋向性。他们描述了一种新的体外模型,用于深入研究 TBEV 诱导的神经发病机制,并提高我们对嗜神经病毒靶向和损伤人脑细胞机制的理解。