DataSheet_1_IFN-β Deficiency Results in Fatal or Demyelinating Disease in C57BL/6 Mice Infected With Theiler’s Murine Encephalomyelitis Viruses.pdf

Type I Interferons (IFN-I) are important inducers of the antiviral immune response and immune modulators. IFN-β is the most highly expressed IFN-I in the central nervous system (CNS). The infection of SJL mice with the BeAn or the DA strain of Theiler’s murine encephalomyelitis virus (TMEV) results in a progressive demyelinating disease. C57BL/6 mice are usually resistant to TMEV-induced demyelination and eliminate these strains from the CNS within several weeks. Using C57BL/6 IFN-β knockout (IFN-β-/-) mice infected with TMEV, we evaluated the role of IFN-β in neuroinfection. Despite the resistance of C57BL/6 wild type (WT) mice to TMEV infection, DA-infected IFN-β-/- mice had to be killed at 7 to 8 days post infection (dpi) due to severe clinical disease. In contrast, BeAn-infected IFN-β-/- mice survived until 98 dpi. Nevertheless at 14 dpi, BeAn-infected IFN-β-/- mice showed a stronger encephalitis and astrogliosis, higher viral load as well as higher mRNA levels of Isg15, Eif2ak2 (PKR), Tnfa, Il1b, Il10, Il12 and Ifng in the cerebrum than BeAn-infected WT mice. Moreover, the majority of IFN-β-/- mice did not clear the virus from the CNS and developed mild demyelination in the spinal cord at 98 dpi, whereas virus and lesions were absent in the spinal cord of WT mice. Persistently infected IFN-β-/- mice also had higher Isg15, Eif2ak1, Tnfa, Il1a, Il1b and Ifng mRNA levels in the spinal cord at 98 dpi than their virus-negative counterparts indicating an activation of IFN-I signaling and ongoing inflammation. Most importantly, BeAn-infected NesCre+/- IFN-βfl/fl mice, which do not express IFN-β in neurons, astrocytes and oligodendrocytes, only developed mild brain lesions similar to WT mice. Consequently, IFN-β produced by neuroectodermal cells does not seem to play a critical role in the resistance of C57BL/6 mice against fatal and demyelinating disease induced by TMEV strains.

I型干扰素（IFN-I）作为抗病毒免疫反应的重要诱导剂及免疫调节剂，在免疫学领域占据着举足轻重的地位。其中，IFN-β在中枢神经系统（CNS）中表达最为显著。SJL小鼠感染贝安或DA株的泰勒鼠脑脊髓炎病毒（TMEV）会导致进行性脱髓鞘疾病。C57BL/6小鼠通常对TMEV诱导的脱髓鞘具有抵抗力，能够在几周内将这些病毒株从CNS中清除。本研究利用感染TMEV的C57BL/6 IFN-β敲除（IFN-β-/-）小鼠，评估了IFN-β在神经感染中的作用。尽管C57BL/6野生型（WT）小鼠对TMEV感染具有抵抗力，但DA感染后的IFN-β-/-小鼠因严重临床疾病，在感染后7至8天（dpi）被迫处死。相比之下，BeAn感染后的IFN-β-/-小鼠存活至98 dpi。然而，在14 dpi时，BeAn感染后的IFN-β-/-小鼠在大脑中表现出比BeAn感染WT小鼠更强的脑炎和星形胶质细胞反应，更高的病毒载量以及Isg15、Eif2ak2（PKR）、Tnfa、Il1b、Il10、Il12和Ifng的mRNA水平。此外，大多数IFN-β-/-小鼠未能从CNS清除病毒，并在98 dpi时在脊髓中发生轻微的脱髓鞘，而WT小鼠的脊髓中则无病毒和病变。持续感染的IFN-β-/-小鼠在98 dpi时，脊髓中的Isg15、Eif2ak1、Tnfa、Il1a、Il1b和Ifng mRNA水平也高于病毒阴性对照小鼠，这表明IFN-I信号通路被激活，炎症持续存在。最重要的是，不表达IFN-β的NesCre+/- IFN-βfl/fl小鼠（这些小鼠在神经元、星形胶质细胞和少突胶质细胞中不表达IFN-β），仅表现出与WT小鼠相似的轻度脑部病变。因此，由神经外胚层细胞产生的IFN-β似乎并未在C57BL/6小鼠对TMEV菌株引起的致命和脱髓鞘疾病的抵抗力中发挥关键作用。