Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Department of Biomedical Sciences, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China.
J Virol. 2020 Nov 9;94(23). doi: 10.1128/JVI.01700-20.
Avian influenza virus (AIV) can cross species barriers to infect humans and other mammals. However, these species-cross transmissions are most often dead-end infections due to host restriction. Current research about host restriction focuses mainly on the barriers of cell membrane, nuclear envelope, and host proteins; whether microRNAs (miRNAs) play a role in host restriction is largely unknown. In this study, we used porcine alveolar macrophage (PAM) cells as a model to elucidate the role of miRNAs in host range restriction. During AIV infection, 40 dysregulation expressed miRNAs were selected in PAM cells. Among them, two (; swine) miRNAs, and , could inhibit the infection and replication of AIV in PAM cells by directly targeting viral genome and inducing cell apoptosis via inhibiting the expression of anti-apoptotic protein HMBOX1. Avian but not swine influenza virus caused upregulated expressions of and in PAM cells. We further found that NF-κB P65 was more effectively phosphorylated upon AIV infection and that P65 functioned as a transcription activator to regulate the AIV-induced expression of Importantly, we found that and could also be specifically upregulated upon AIV infection in newborn pig tracheal epithelial (NPTr) cells and also exerted anti-AIV function. In summary, our study indicated that miRNAs act as a host barrier during cross-species infection of influenza A virus. The host range of an influenza A virus is determined by species-specific interactions between virus and host cell factors. Host miRNAs can regulate influenza A virus replication; however, the role of miRNAs in host species specificity is unclear. Here, we show that the induced expression of and in swine cells is modulated by NF-κB P65 phosphorylation in response to AIV infection but not swine influenza virus infection. and exerted antiviral function via targeting viral RNAs and causing apoptosis by inhibiting the expression of HMBOX1 in host cells. These findings uncover miRNAs as a host range restriction factor that limits cross-species infection of influenza A virus.
禽流感病毒（AIV）可以跨越物种屏障感染人类和其他哺乳动物。然而，由于宿主限制，这些跨物种传播通常是死胡同感染。目前关于宿主限制的研究主要集中在细胞膜、核膜和宿主蛋白的障碍上；miRNAs 是否在宿主限制中发挥作用还知之甚少。在这项研究中，我们使用猪肺泡巨噬细胞（PAM）细胞作为模型，阐明 miRNAs 在宿主范围限制中的作用。在 AIV 感染期间，在 PAM 细胞中选择了 40 个失调表达的 miRNAs。其中，两个（猪）miRNAs，和，可通过直接靶向病毒基因组并通过抑制抗凋亡蛋白 HMBOX1 的表达诱导细胞凋亡，从而抑制 AIV 在 PAM 细胞中的感染和复制。禽而非猪流感病毒会导致 PAM 细胞中上调表达和。我们进一步发现，AIV 感染后 NF-κB P65 的磷酸化更有效，并且 P65 作为转录激活因子通过调节 AIV 诱导的表达起作用。重要的是，我们发现和也可以在新生猪气管上皮（NPTr）细胞中被 AIV 感染特异性上调，并发挥抗 AIV 作用。总之，我们的研究表明，miRNAs 在流感 A 病毒的跨物种感染中起宿主屏障作用。流感 A 病毒的宿主范围由病毒和宿主细胞因子之间的特定物种相互作用决定。宿主 miRNAs 可以调节流感 A 病毒的复制；然而，miRNAs 在宿主物种特异性中的作用尚不清楚。在这里，我们表明，猪细胞中诱导表达和是由 NF-κB P65 磷酸化调节的，响应 AIV 感染而不是猪流感病毒感染。和通过靶向病毒 RNA 并通过抑制宿主细胞中 HMBOX1 的表达发挥抗病毒作用。这些发现揭示了 miRNAs 作为限制流感 A 病毒跨物种感染的宿主范围限制因子。
