Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA.
Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.00071-20.
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 log 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. 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.
天然免疫系统通常针对入侵病原体进行即时但短暂的上调反应，干扰素 (IFN)-刺激基因 (ISG) 的激活是其主要特征。相比之下，慢性天然免疫系统激活通常与自身免疫和广泛的自身炎症性疾病相关，其中包括干扰素病。在这里，我们研究了一种具有终生天然免疫系统过度激活的转基因小鼠模型中的逆转录病毒易感性。这些小鼠通过转基因低水平表达微小 RNA 依赖性 RNA 聚合酶 (RdRP)，该聚合酶合成双链 RNA，被黑色素瘤分化相关蛋白 5 (MDA5) 识别，从而引发许多 ISG 的组成型上调。然而，与众多人类和小鼠 ISG 过度激活的范例形成鲜明对比的是，包括 MDA5 的组成型激活，它们缺乏自身炎症的后遗症。RdRP 转基因小鼠（RdRP 小鼠）抵抗几种致病 RNA 和 DNA 病毒感染和疾病。然而，逆转录病毒通过其他机制被感知，在宿主中持续存在，并具有独特的复制和免疫逃避特性。我们用各种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、病毒载量以及脾和骨髓中多种靶细胞类型的感染均显著减少。在慢性感染期间，RdRP 小鼠的循环病毒 RNA 比 WT 小鼠低 2.35±0.66 log。保护需要持续的 I 型 IFN 信号。结果表明，重构的 RdRP 小鼠天然免疫系统大大降低了逆转录病毒的复制、设定点和发病机制。逆转录病毒的免疫控制非常困难，这是 HIV-1 大流行中最具临床意义的根本问题。随着人类进一步进入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增加。天然免疫系统（包括 ISG）在控制逆转录病毒感染中的作用目前是一个研究热点。这项工作提供了证据，证明预先激活的天然免疫系统是抵抗逆转录病毒发病机制的有效防御，从而降低病毒复制和疾病负担。RdRP 小鼠的 Friend 逆转录病毒 (FV) 血症也明显降低。这些结果可能对利用 ISG 反应来降低人类逆转录病毒病原体的传播或控制发病机制具有重要意义。
