■甲型流感病毒(IAV)感染是一种全球性的呼吸道疾病,每年导致3-5百万例严重疾病,导致290,000-650,000人死亡。此外,在过去的一个世纪里,四次全球IAV大流行夺走了数百万人的生命。气管的上皮衬里在IAV感染中起着至关重要的作用,作为病毒进入和复制点以及在抗病毒免疫应答。人类患者通常无法进入气管组织,这使得动物模型对于研究气管宿主免疫反应至关重要。
■在这项研究中,对猪接种适应猪或人的H1N1IAV,以了解宿主对IAV的适应如何在感染过程中塑造先天免疫反应。对上气管组织和下气管组织中的宿主反应进行了深入的多组学分析(全局蛋白质组学和RNA测序),并通过微流体qPCR对结果进行验证。此外,选择了一部分样本进行组织病理学检查.
■与猪或人适应的IAV感染后,在上气管和下气管中诱导了经典的先天抗病毒免疫反应,基因上调,与病毒感染和识别相关的蛋白质丰度更高。伴随着干扰素刺激基因的显著诱导,相应的蛋白质浓度较高。与在下气管中感染人适应的IAV株相比,用猪适应的病毒感染诱导了更强的免疫反应,这可能是较高的病毒载量和较高程度的炎症的结果。
■JAK-STAT途径的核心组成部分,凋亡,嘧啶代谢,根据猪或人适应的病毒感染,细胞骨架发生了显着变化,这可能是与针对假定的人畜共患IAV的抗病毒免疫有关的机制。根据我们的发现,我们假设在宿主适应期间,IAV进化以调节重要的宿主细胞元件以有利于病毒感染性和复制。
UNASSIGNED: Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response.
UNASSIGNED: In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination.
UNASSIGNED: A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation.
UNASSIGNED: Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.