The innate immune system is normally programmed for immediate but transient upregulation in response to invading pathogens, and interferon (IFN)-stimulated gene (ISG) activation is a central feature. In contrast, chronic innate immune system activation is typically associated with autoimmunity and a broad array of autoinflammatory diseases that include the interferonopathies. Here, we studied retroviral susceptibility in a transgenic mouse model with lifelong innate immune system hyperactivation. The mice transgenically express low levels of a picornaviral RNA-dependent RNA polymerase (RdRP), which synthesizes double-stranded RNAs that are sensed by melanoma differentiation-associated protein 5 (MDA5) to trigger constitutive upregulation of many ISGs. However, in striking counterpoint to the paradigm established by numerous human and murine examples of ISG hyperactivation, including constitutive MDA5 activation, they lack autoinflammatory sequelae. RdRP-transgenic mice (RdRP mice) resist infection and disease caused by several pathogenic RNA and DNA viruses. However, retroviruses are sensed through other mechanisms, persist in the host, and have distinctive replication and immunity-evading properties. We infected RdRP mice and wild-type (WT) mice with various doses of a pathogenic retrovirus (Friend virus) and assessed immune parameters and disease at 1, 4, and 8 weeks. Compared to WT mice, RdRP mice had significantly reduced splenomegaly, viral loads, and infection of multiple target cell types in the spleen and the bone marrow. During chronic infection, RdRP mice had 2.35 ± 0.66 log10 lower circulating viral RNA than WT. Protection required ongoing type I IFN signaling. The results show that the reconfigured RdRP mouse innate immune system substantially reduced retroviral replication, set point, and pathogenesis.IMPORTANCE Immune control of retroviruses is notoriously difficult, a fundamental problem that has been most clinically consequential with the HIV-1 pandemic. As humans expand further into previously uninhabited areas, the likelihood of new zoonotic retroviral exposures increases. The role of the innate immune system, including ISGs, in controlling retroviral infections is currently an area of intensive study. This work provides evidence that a primed innate immune system is an effective defense against retroviral pathogenesis, resulting in reduced viral replication and burden of disease outcomes. RdRP mice also had considerably lower Friend retrovirus (FV) viremia. The results could have implications for harnessing ISG responses to reduce transmission or control pathogenesis of human retroviral pathogens.

中文翻译：

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病毒 RdRP 的系统表达可预防逆转录病毒感染和疾病。

先天免疫系统通常会针对入侵的病原体进行立即但短暂的上调，而干扰素 (IFN) 刺激的基因 (ISG) 激活是一个核心特征。相反，慢性先天免疫系统激活通常与自身免疫和包括干扰素病在内的多种自身炎症性疾病相关。在这里，我们研究了终生先天免疫系统过度激活的转基因小鼠模型中的逆转录病毒敏感性。这些小鼠转基因表达低水平的小RNA病毒RNA依赖性RNA聚合酶（RdRP），该酶合成双链RNA，黑色素瘤分化相关蛋白5（MDA5）感知这些双链RNA，从而触发许多ISG的组成性上调。然而，与许多人类和小鼠 ISG 过度激活（包括组成型 MDA5 激活）实例所建立的范式形成鲜明对比，它们缺乏自身炎症后遗症。RdRP 转基因小鼠（RdRP 小鼠）可抵抗多种致病性 RNA 和 DNA 病毒引起的感染和疾病。然而，逆转录病毒通过其他机制被感知，在宿主体内持续存在，并具有独特的复制和免疫逃避特性。我们用不同剂量的致病性逆转录病毒（Friend 病毒）感染 RdRP 小鼠和野生型 (WT) 小鼠，并在 1、4 和 8 周时评估免疫参数和疾病。与 WT 小鼠相比，RdRP 小鼠的脾肿大、病毒载量以及脾脏和骨髓中多种靶细胞类型的感染显着减少。在慢性感染期间，RdRP 小鼠的循环病毒 RNA 比 WT 低 2.35 ± 0.66 log10。保护需要持续的 I 型干扰素信号传导。结果表明，重新配置的 RdRP 小鼠先天免疫系统大大减少了逆转录病毒的复制、设定点和发病机制。 重要性 众所周知，逆转录病毒的免疫控制非常困难，这是 HIV-1 大流行在临床上最严重的一个基本问题。随着人类进一步扩展到以前无人居住的地区，新的人畜共患逆转录病毒暴露的可能性就会增加。先天免疫系统（包括 ISG）在控制逆转录病毒感染中的作用是目前深入研究的领域。这项工作提供的证据表明，启动的先天免疫系统可以有效防御逆转录病毒发病机制，从而减少病毒复制和疾病结果的负担。RdRP 小鼠的 Friend 逆转录病毒 (FV) 病毒血症也显着降低。这些结果可能对利用 ISG 反应来减少人类逆转录病毒病原体的传播或控制发病机制产生影响。