Data_Sheet_1_Defective Viral Particles Produced in Mast Cells Can Effectively Fight Against Lethal Influenza A Virus.docx

Mast cells play an important role in the pathogenesis of highly pathogenic H5N1 avian influenza virus (H5N1-HPAIV) infection. Defective viral particles (DPs) can interfere with the replication of infectious viruses and stimulate the innate immune response of host cells. However, DPs arising from mast cells during HPAIV replication and their potent antiviral actions has not been reported. Here, we showed that the human mastocytoma cell line, HMC-1, allowed for the productive replication of the H5N1-HPAIV. Compared with alveolar cell line A549, DPs were propagated preferentially and abundantly in mast cells following IAV infection, which can be attributed to the wide existence of Argonaute 2 (AGO2) in HMC-1 cells. In addition, DPs generated in H5N1-infected cells could provide great therapeutic protection on mice to fight against various influenza A viruses, which included not only homologous H5N1-HPAIV, but also heterologous H1N1, H3N2, H7N2, and H9N2. Importantly, DPs generated in H5N1-infected HMC-1 cells could diminish viral virulence in vivo and in vitro by triggering a robust antiviral response through type II interferon signaling pathways. This study is the first to illustrate the arising of DPs in H5N1-HPAIV infected mast cells and explore their favorable ability to protect mice from influenza A viruses infection, which provides a novel insight and valuable information for the progress of new strategies to fight influenza A viruses infection, especially highly pathogenic avian influenza virus infection by focusing on the DPs generated in mast cells.

肥大细胞在高致病性H5N1禽流感病毒（highly pathogenic H5N1 avian influenza virus, H5N1-HPAIV）感染的发病机制中发挥重要作用。缺陷病毒颗粒（Defective viral particles, DPs）可干扰感染性病毒的复制，并激活宿主细胞的固有免疫应答。然而，在HPAIV复制过程中由肥大细胞产生的DPs及其强效抗病毒作用尚未见报道。本研究证实，人肥大细胞瘤细胞系HMC-1可支持H5N1-HPAIV的有效复制。与肺泡细胞系A549相比，甲型流感病毒（Influenza A virus, IAV）感染后，DPs在肥大细胞中更优先且大量增殖，这一现象可归因于Argonaute 2 (AGO2) 在HMC-1细胞中的广泛表达。此外，在H5N1病毒感染细胞中产生的DPs可对小鼠提供优异的治疗保护作用，使其抵御多种甲型流感病毒的感染，涵盖同源的H5N1-HPAIV，以及异源的H1N1、H3N2、H7N2和H9N2亚型。尤为关键的是，在H5N1感染的HMC-1细胞中产生的DPs可通过激活II型干扰素信号通路引发强烈的抗病毒应答，从而在体内外降低病毒毒力。本研究首次阐明了H5N1-HPAIV感染的肥大细胞中DPs的产生，并探究了其保护小鼠抵御甲型流感病毒感染的优异能力，为开发抗甲型流感病毒感染（尤其是高致病性禽流感病毒感染）的新型防治策略提供了全新的视角与有价值的参考依据，研究聚焦于肥大细胞来源的DPs。