Differential tropisms of old and new world hantaviruses influence virulence and developing host-directed antiviral candidates

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.