Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Department of Biochemistry, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem, Israel.
J Virol. 2021 Jun 24;95(14):e0013021. doi: 10.1128/JVI.00130-21.
The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues , coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.
鼻黏膜构成了呼吸道病毒（包括严重急性呼吸综合征冠状病毒 2（SARS-CoV-2））的主要进入部位。虽然对终末期 COVID-19 的不平衡先天免疫反应已经进行了广泛研究，但 SARS-CoV-2 在黏膜进入部位的早期感染阶段仍未得到探索。在这里，我们采用 SARS-CoV-2 和流感病毒感染天然多细胞类型的人鼻鼻甲和肺组织，结合全基因组转录分析，研究病毒易感性和局部黏膜先天免疫反应的早期模式在人体呼吸道的真实环境中。SARS-CoV-2 有效地感染了鼻鼻甲组织，主要靶向呼吸上皮细胞，组织相关的亚基因组 mRNA 快速增加，并分泌传染性病毒后代。重要的是，SARS-CoV-2 感染在鼻黏膜中引发了强大的抗病毒和炎症先天免疫反应。干扰素刺激基因、细胞因子和趋化因子的上调与干扰素信号和免疫细胞激活途径有关，比流感病毒感染引发的上调更为广泛。相反，肺组织对 SARS-CoV-2 的先天免疫反应受到限制，I 型和 III 型干扰素的上调明显缺乏，与它们对流感病毒的强烈先天免疫反应形成对比。我们的发现揭示了上呼吸道和下呼吸道中针对 SARS-CoV-2 的不同组织特异性先天免疫反应。这些研究阐明了鼻黏膜在病毒传播和免疫防御中的作用，暗示了早期干预的机会窗口，而 SARS-CoV-2 感染早期肺组织中先天免疫反应的受限可能是 COVID-19 晚期独特的不受控制的肺部损伤的基础。为了降低 COVID-19 的晚期发病率和死亡率，有必要更好地了解和针对人体呼吸道中 SARS-CoV-2 感染的最早阶段。在这里，我们研究了 SARS-CoV-2 感染的初始步骤以及在人鼻黏膜和肺组织的天然多细胞复杂性中随之而来的先天免疫反应。通过比较平行感染 SARS-CoV-2 和流感病毒的鼻和肺组织的全球先天反应模式，我们发现上呼吸道和下呼吸道之间存在明显的病毒-宿主相互作用，这可能决定 SARS-CoV-2 感染的结果和独特的发病机制。在鼻黏膜感染模型中的研究可以用于评估病毒进化变化的影响，并评估针对 SARS-CoV-2 和其他人类呼吸道病原体的新治疗和预防措施。
