Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Virol. 2012 Dec;86(23):12655-64. doi: 10.1128/JVI.01564-12. Epub 2012 Sep 12.
Noroviruses (NVs) cause the majority of cases of epidemic nonbacterial gastroenteritis worldwide and contribute to endemic enteric disease. However, the molecular mechanisms responsible for immune control of their replication are not completely understood. Here we report that the transcription factor interferon regulatory factor 1 (IRF-1) is required for control of murine NV (MNV) replication and pathogenesis in vivo. This led us to studies documenting a cell-autonomous role for IRF-1 in gamma interferon (IFN-γ)-mediated inhibition of MNV replication in primary macrophages. This role of IRF-1 in the inhibition of MNV replication by IFN-γ is independent of IFN-αβ signaling. While the signal transducer and activator of transcription STAT-1 was also required for IFN-γ-mediated inhibition of MNV replication in vitro, class II transactivator (CIITA), interferon regulatory factor 3 (IRF-3), and interferon regulatory factor 7 (IRF-7) were not required. We therefore hypothesized that there must be a subset of IFN-stimulated genes (ISGs) regulated by IFN-γ in a manner dependent only on STAT-1 and IRF-1. Analysis of transcriptional profiles of macrophages lacking various transcription factors confirmed this hypothesis. These studies identify a key role for IRF-1 in IFN-γ-dependent control of norovirus infection in mice and macrophages.
诺如病毒（NVs）导致了全球大多数爆发性非细菌性胃肠炎病例，并导致了地方性肠道疾病。然而，负责免疫控制其复制的分子机制尚不完全清楚。在这里，我们报告转录因子干扰素调节因子 1（IRF-1）是控制鼠诺如病毒（MNV）在体内复制和发病机制所必需的。这促使我们进行了研究，记录了 IRF-1 在γ干扰素（IFN-γ）介导的抑制 MNV 在原代巨噬细胞中的复制中的细胞自主作用。IRF-1 在 IFN-γ抑制 MNV 复制中的这种作用独立于 IFN-αβ信号传导。虽然信号转导和转录激活因子 STAT-1 也需要体外 IFN-γ介导的抑制 MNV 复制，但 II 类转录激活物（CIITA）、干扰素调节因子 3（IRF-3）和干扰素调节因子 7（IRF-7）则不需要。因此，我们假设一定有一组 IFN 刺激基因（ISGs）通过仅依赖于 STAT-1 和 IRF-1 的方式被 IFN-γ调控。对缺乏各种转录因子的巨噬细胞的转录谱分析证实了这一假设。这些研究确定了 IRF-1 在 IFN-γ依赖性控制小鼠和巨噬细胞中诺如病毒感染中的关键作用。
