Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Virol. 2019 Sep 30;93(20). doi: 10.1128/JVI.00559-19. Print 2019 Oct 15.
Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level. We found that the number of viruses infecting a cell (multiplicity of infection [MOI]) influences the magnitude of virus antagonism of the host innate antiviral response. Infections performed at high MOIs resulted in increased viral gene expression per cell and stronger antagonist effect than infections at low MOIs. In addition, single-cell patterns of expression of interferons (IFN) and IFN-stimulated genes (ISGs) provided important insights into the contributions of the infected and bystander cells to the innate immune responses during infection. Specifically, the expression of multiple ISGs was lower in infected than in bystander cells. In contrast with other IFNs, IFN lambda 1 (IFNL1) showed a widespread pattern of expression, suggesting a different cell-to-cell propagation mechanism more reliant on paracrine signaling. Finally, we measured the dynamics of the antiviral response in primary human epithelial cells, which highlighted the importance of early innate immune responses at inhibiting virus spread. Influenza A virus (IAV) is a respiratory pathogen of high importance to public health. Annual epidemics of seasonal IAV infections in humans are a significant public health and economic burden. IAV also causes sporadic pandemics, which can have devastating effects. The main target cells for IAV replication are epithelial cells in the respiratory epithelium. The cellular innate immune responses induced in these cells upon infection are critical for defense against the virus, and therefore, it is important to understand the complex interactions between the virus and the host cells. In this study, we investigated the innate immune response to IAV in the respiratory epithelium at the single-cell level, providing a better understanding on how a population of epithelial cells functions as a complex system to orchestrate the response to virus infection and how the virus counteracts this system.
流感病毒 (IAV) 与呼吸道上皮的早期相互作用可能决定感染的结果。对全球细胞固有免疫反应的研究往往掩盖了细胞群体作为有组织和异质系统工作以抵抗病毒感染的机制的多个方面，以及病毒如何对抗这些系统。在这项研究中，我们在单细胞水平上实验性地剖析了 IAV 和人呼吸道上皮细胞在早期感染过程中的相互作用。我们发现，感染细胞的病毒数量（感染复数 [MOI]）影响病毒对抗宿主固有抗病毒反应的程度。在高 MOI 下进行的感染导致每个细胞的病毒基因表达增加，并且比在低 MOI 下进行的感染具有更强的拮抗剂作用。此外，干扰素 (IFN) 和 IFN 刺激基因 (ISG) 的单细胞表达模式为感染期间受感染和旁观者细胞对固有免疫反应的贡献提供了重要的见解。具体而言，与旁观者细胞相比，受感染细胞中多种 ISG 的表达水平较低。与其他 IFNs 不同，IFN lambda 1 (IFNL1) 表现出广泛的表达模式，表明存在更依赖旁分泌信号的不同细胞间传播机制。最后，我们测量了原代人上皮细胞中抗病毒反应的动力学，这突出了早期固有免疫反应在抑制病毒传播方面的重要性。流感病毒 (IAV) 是对公共卫生具有高度重要性的呼吸道病原体。每年在人类中发生的季节性 IAV 感染流行是一个重大的公共卫生和经济负担。IAV 还会引起零星的大流行，这可能会产生毁灭性的影响。IAV 复制的主要靶细胞是呼吸道上皮中的上皮细胞。感染这些细胞后诱导的细胞固有免疫反应对于防御病毒至关重要，因此，了解病毒与宿主细胞之间的复杂相互作用非常重要。在这项研究中，我们在单细胞水平上研究了呼吸道上皮细胞中的 IAV 固有免疫反应，为了解呼吸道上皮细胞群体作为一个复杂系统如何发挥作用以协调对病毒感染的反应以及病毒如何对抗该系统提供了更好的认识。
