ABSTRACT

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

摘要

流感病毒或 SARS-CoV-2 等病毒的大流行与高发病率和死亡率有关，因此对全球健康和经济构成巨大威胁。需要生理相关模型来研究病毒生命周期，描述病毒感染的病理生理后果，并探索可能的药物靶点和治疗方案。虽然简单的基于细胞培养的模型不能反映组织环境和系统反应，但动物模型与巨大的直接和间接成本以及伦理问题有关。离体基于组织外植体的平台已被引入作为合适的平台，以弥合细胞培养和动物模型之间的差距。我们为两种呼吸道病毒 A 型流感病毒 (IAV) 和 SARS-CoV-2 建立了鼠肺组织外植体平台。我们观察到有效的病毒复制，与炎性细胞因子的释放和抗病毒干扰素反应的诱导相关，与人肺外植体中的离体感染相当。内溶酶体进入可被确认为药物干预的潜在宿主靶标，并且先前在体外观察到的用于宿主定向治疗的氟西汀和干扰素的潜在再利用潜力可在离体模型中重现。