A skin organoid-based infection platform identifies an inhibitor specific for HFMD

Jun Li, Jie Ma, Ruiyuan Cao, Qiyu Zhang, Mansheng Li, Wenwen Wang, Yujie Wang, Wei Li, Yunping Zhu and Ling Leng ()
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Jun Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Jie Ma: Beijing Institute of Lifeomics
Ruiyuan Cao: Beijing Institute of Pharmacology and Toxicology
Qiyu Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Mansheng Li: Beijing Institute of Lifeomics
Wenwen Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yujie Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Wei Li: Beijing Institute of Pharmacology and Toxicology
Yunping Zhu: Beijing Institute of Lifeomics
Ling Leng: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The EV-A71 poses a serious threat to the health and lives of children. The EV-A71 can be transmitted by direct and indirect skin contact. Therefore, there is an urgent need to create novel skin models using human-derived cells to study the biology and pathogenesis of the virus and facilitate drug screening. Here, we use human induced pluripotent stem cells-derived skin organoids (hiPSC-SOs) as a model for EV-A71 infection and find that multiple cell types within the skin organoids, including epidermal cells, hair follicle cells, fibroblasts, and nerve cells, express EV-A71 receptors and are susceptible to EV-A71 infection. We elucidate the specific response of different cell types to EV-A71 and reveal that EV-A71 infection can degrade extracellular collagen and affect fibroblasts. We find that EV-A71 can mediate epidermal cell damage through autophagy and Integrin/Hippo-YAP/TAZ signaling pathways, thereby promoting hyperproliferation of progenitor cells. Based on this finding, we identify an autophagy-associated protein as a drug target of EV-A71 and discover an EV-A71 replication inhibitor. Altogether, these data suggest that hiPSC-SOs can be used as an infectious disease model to study skin infectious diseases, providing a valuable resource for drug screening to identify candidate virus therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-57610-2

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