Rissmann Melanie, Noack Danny, Spliethof Thomas M, Vaes Vincent P, Stam Rianne, van Run Peter, Clark Jordan J, Verjans Georges M G M, Haagmans Bart L, Krammer Florian, Koopmans Marion P G, van den Brand Judith M A, Rockx Barry
Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.
Division of Pathology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
PLoS Pathog. 2025 Jan 22;21(1):e1012875. doi: 10.1371/journal.ppat.1012875. eCollection 2025 Jan.
Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is an unmet need for an in vivo model to study infection of different orthohantaviruses in physiologically relevant tissue and to assess the efficacy of novel pan-orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft mouse model to study the permissiveness for different orthohantavirus species and to assess its utility for preclinical testing of therapeutics. Following infection of xenografted human lung tissues, distinct orthohantavirus species differentially replicated in the human lung and subsequently spread systemically. The different orthohantaviruses primarily targeted the endothelium, respiratory epithelium and macrophages in the human lung. A proof-of-concept preclinical study showed treatment of these mice with a virus neutralizing antibody could block Andes orthohantavirus infection and dissemination. This pan-orthohantavirus model will facilitate progress in the fundamental understanding of pathogenesis and virus-host interactions for orthohantaviruses. Furthermore, it is an invaluable tool for preclinical evaluation of novel candidate pan-orthohantavirus intervention strategies.
正汉坦病毒是新兴的人畜共患病毒，可通过呼吸道感染人类。目前迫切需要一种体内模型，用于研究不同正汉坦病毒在生理相关组织中的感染情况，并评估新型泛正汉坦病毒应对措施的疗效。在此，我们描述了一种人肺异种移植小鼠模型的应用，用于研究不同正汉坦病毒种类的易感性，并评估其在治疗药物临床前测试中的效用。在异种移植的人肺组织感染后，不同的正汉坦病毒种类在人肺中差异复制，随后全身扩散。不同的正汉坦病毒主要靶向人肺中的内皮细胞、呼吸道上皮细胞和巨噬细胞。一项概念验证性临床前研究表明，用病毒中和抗体治疗这些小鼠可阻断安第斯正汉坦病毒的感染和传播。这种泛正汉坦病毒模型将有助于在对正汉坦病毒发病机制和病毒-宿主相互作用的基础理解方面取得进展。此外，它是新型泛正汉坦病毒干预策略临床前评估的宝贵工具。
