Reagents and resources used in this study.

Hantaviruses are zoonotically transmitted from rodents to humans through the respiratory route, with no currently approved antivirals or widely available vaccines. The recent discovery of interhuman-transmitted Andes virus (ANDV) necessitates the systematic identification of cell tropism, infective potential, and potent therapeutic agents. We utilized human primary lung endothelial cells, various pluripotent stem cell-derived heart and brain cell types, and established human lung organoid models to evaluate the tropisms of Old World Hantaan (HTNV) and New World ANDV and Sin Nombre (SNV) viruses. ANDV exhibited broad tropism for all cell types assessed. SNV readily infected pulmonary endothelial cells, while HTNV robustly amplified in endothelial cells, cardiomyocytes, and astrocytes. We also provide the first evidence of hantaviral infection in human 3D distal lung organoids, which effectively modeled these differential tropisms. ANDV infection transcriptionally promoted cell injury and inflammatory responses, and downregulated lipid metabolic pathways in lung epithelial cells. Evaluation of selected drug candidates and pharmacotranscriptomics revealed that the host-directed small molecule compound urolithin B inhibited ANDV infection and restored cellular metabolism with minimal changes in host transcription. Given the scarcity of academic BSL-4 facilities that enable in vivo hantaviral studies, this investigation presents advanced human cell-based model systems that closely recapitulate host cell tropism and responses to infection, thereby providing critical platforms to evaluate potential antiviral drug candidates.

汉坦病毒（Hantaviruses）经呼吸道途径在啮齿动物与人类之间发生动物源性传播，目前尚无获批的抗病毒药物或广泛可用的疫苗。近期发现可发生人际传播的安第斯病毒（Andes virus, ANDV），亟需系统性开展其细胞嗜性（cell tropism）、感染潜能及强效治疗药物的鉴定工作。本研究利用人原代肺内皮细胞、多种多能干细胞分化而来的心脏与脑细胞类型，以及已构建的人肺类器官模型，对旧世界汉滩病毒（Hantaan virus, HTNV）、新世界安第斯病毒及辛诺柏病毒（Sin Nombre virus, SNV）的嗜性进行评估。结果显示，安第斯病毒在所有检测的细胞类型中均展现出广泛的细胞嗜性；辛诺柏病毒可高效感染肺内皮细胞，而汉滩病毒则能在内皮细胞、心肌细胞及星形胶质细胞中实现高效增殖。本研究还首次提供了汉坦病毒感染人类3D远端肺类器官的证据，该模型可有效复现上述不同的病毒嗜性特征。安第斯病毒感染可在转录层面促进肺上皮细胞的细胞损伤与炎症应答，并下调其脂质代谢通路。通过对候选药物进行筛选及药物转录组学（pharmacotranscriptomics）分析，本研究发现宿主靶向小分子化合物鞣花丹宁B（urolithin B）可抑制安第斯病毒感染，并恢复细胞代谢，且对宿主转录组的影响极小。鉴于可开展汉坦病毒体内研究的学术机构可用生物安全四级（BSL-4）实验室资源稀缺，本研究构建的先进人类细胞模型体系可精准复现宿主细胞嗜性与感染应答，从而为潜在抗病毒候选药物的评估提供关键研究平台。