ABSTRACT

St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne flavivirus that causes severe neurological disease in humans. SLEV replication in the central nervous system (CNS) induces the local production of interferons (IFNs), which are attributed to host protection. The antiviral response to SLEV infection in the CNS is not completely understood, which led us to characterize the roles of IFNs using mouse models of St. Louis encephalitis. We infected mice deficient in type I IFN receptor (ABR^−/-) or deficient in Type II IFN (IFNγ^−/-) and assessed the contribution of each pathway to disease development. We found that type I and II IFNs play different roles in SLEV infection. Deficiency in type I IFN signaling was associated to an early and increased mortality, uncontrolled SLEV replication and impaired ISG expression, leading to increased proinflammatory cytokine production and brain pathology. Conversely, IFNγ^−/- mice were moderately resistant to SLEV infection. IFNγ deficiency caused no changes to viral load or SLEV-induced encephalitis and did not change the expression of ISGs in the brain. We found that type I IFN is essential for the control of SLEV replication whereas type II IFN was not associated with protection in this model.

摘要

圣路易斯脑炎病毒 (SLEV) 是一种被忽视的蚊媒黄病毒，可导致人类严重的神经系统疾病。中枢神经系统 (CNS) 中的 SLEV 复制诱导干扰素 (IFN) 的局部产生，这归因于宿主保护。对 CNS 中 SLEV 感染的抗病毒反应尚不完全清楚，这导致我们使用圣路易斯脑炎小鼠模型来表征 IFN 的作用。我们感染了缺乏 I 型 IFN 受体 (ABR ^-/- ) 或缺乏 II 型 IFN (IFNγ ^-/- ) 的小鼠) 并评估每个途径对疾病发展的贡献。我们发现 I 型和 II 型干扰素在 SLEV 感染中发挥不同的作用。I 型 IFN 信号缺乏与早期死亡率增加、SLEV 复制不受控制和 ISG 表达受损有关，导致促炎细胞因子的产生和脑病理增加。相反，IFNγ ^-/-小鼠对SLEV感染具有中度抗性。IFNγ缺乏不会导致病毒载量或SLEV诱导的脑炎发生变化，也不会改变大脑中ISG的表达。我们发现 I 型 IFN 对于控制 SLEV 复制至关重要，而 II 型 IFN 在该模型中与保护无关。