{
  "abstract": "Background Hepatitis E virus (HEV), the leading global cause of acute viral hepatitis, lacks robust in vitro models for virology and pathogenesis research.Objective We evaluated induced pluripotent stem cell (iPSC)-induced human liver, intestinal and brain organoids (hLOs, hIOs and hBOs) as platforms for HEV infection and replication.Methods Multilineage organoids were infected with clinical HEV genotypes 1, 3 and 4. Viral tropism, host responses and antiviral efficacy were assessed.Results All organoids supported the complete life cycle of HEV. hLOs exhibited infection in hepatocytes, cholangiocytes, macrophages and stellate cells, accompanied by elevated interleukin-6 levels, impaired hepatic function (reduced secretion of albumin and Factor IX) and increased levels of alanine aminotransferase and aspartate aminotransferase, indicating hepatocellular injury. hIOs demonstrated broad epithelial (enterocyte, goblet, Paneth and endocrine) and mesenchymal infection, with disrupted barrier function (loss of tight junction proteins), proinflammatory cytokines upregulation and initiation of epithelial–mesenchymal transition. hBOs showed neuronal tropism, infecting glutamatergic, dopaminergic and GABAergic neurons, as well as astrocytes and oligodendrocytes. An increased number of TH + dopaminergic neurons was observed. Ribavirin treatment in all three models partially reversed this phenotype.Conclusion This study established iPSC-induced multilineage organoid infection models, confirming HEV’s capacity for pan-tissue infection and revealing potential pathogenic mechanisms in the liver, intestine and nervous system. This platform provides valuable tools for HEV virology research and antiviral drug development, underscoring the unique value of organoid technology in infectious disease research.",
  "authors": [
    {
      "affiliations": [
        "Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, State Key laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, China"
      ],
      "name": "Fan Liu"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Tianxu Liu"
    },
    {
      "affiliations": [
        "Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, State Key laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, China"
      ],
      "name": "Xi Wu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, China"
      ],
      "name": "Zihao Yu"
    },
    {
      "affiliations": [
        "Institute of Medical Biology, Chinese Academay of Medical Sciences and Peking Union Medical College, Kunming, China"
      ],
      "name": "Jincheng Tong"
    },
    {
      "affiliations": [
        "Department of Developmental and Regenerative biology, iORGANtech Limited Company, Jiangsu, China"
      ],
      "name": "Lili Wang"
    },
    {
      "affiliations": [
        "Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, State Key laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, China"
      ],
      "name": "Chenyan Zhao"
    },
    {
      "affiliations": [
        "Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, State Key laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, China"
      ],
      "name": "Jianhui Nie"
    },
    {
      "affiliations": [
        "Institute of Medical Biology, Chinese Academay of Medical Sciences and Peking Union Medical College, Kunming, China"
      ],
      "name": "Youchun Wang"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Kai Wang"
    },
    {
      "affiliations": [
        "Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Lin Bai"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Pengyan Xia"
    },
    {
      "affiliations": [
        "Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Kai Wang"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Guochao Wei"
    },
    {
      "affiliations": [
        "State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, China"
      ],
      "name": "Zi-Zheng Zheng"
    },
    {
      "affiliations": [
        "Department of Developmental and Regenerative biology, iORGANtech Limited Company, Jiangsu, China",
        "Tianjin Key Laboratory of Early Druggability Evaluation of Innovative Drugs and Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China"
      ],
      "name": "Di Wu"
    },
    {
      "affiliations": [
        "Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, State Key laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, China"
      ],
      "name": "Weijin Huang"
    },
    {
      "affiliations": [
        "Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, China"
      ],
      "name": "Lin Wang"
    }
  ],
  "title": "iPSC-induced multilineage liver organoids, small intestinal organoids and brain organoids sustain pangenotype hepatitis E virus propagation",
  "uid": "4d532811-4bf8-5c19-b39d-6d4ae1b9aa92"
}