Severe enterovirus A71 pathogenesis and immune responses in human nucleolin transgenic mice

被引：0

作者：

Nien-En Hsiao ^{[1
]}

Ya-Fang Wang ^{[2
]}

Yi-Chen Lin ^{[1
]}

Wei-Ting Chou ^{[1
]}

Li-Jin Hsu ^{[1
]}

Shih-Min Wang ^{[3
]}

Jen-Ren Wang ^{[4
]}

Ming-Derg Lai ^{[4
]}

Shun-Hua Chen ^{[5
]}

Chuan-Fa Chang ^{[6
]}

机构：

[1] National Cheng Kung University,Department of Medical Laboratory Science and Biotechnology, College of Medicine

[2] National Health Research Institutes,National Institute of Infectious Diseases and Vaccinology

[3] National Cheng Kung University,Institute of Basic Medical Sciences, College of Medicine

[4] National Cheng Kung University,Center of Infectious Disease and Signaling Research

[5] National Cheng Kung University,School of Medicine, College of Medicine

[6] National Cheng Kung University Hospital,Center for Infection Control, College of Medicine

[7] National Cheng Kung University,Department of Biochemistry and Molecular Biology, College of Medicine

[8] National Cheng Kung University,Department of Microbiology and Immunology, College of Medicine

[9] National Cheng Kung University,undefined

来源：

Medical Microbiology and Immunology | 2025年 / 214卷 / 1期

关键词：

Enterovirus A71; Nucleolin; Transgenic mice;

D O I：

10.1007/s00430-025-00842-2

中图分类号：

学科分类号：

摘要：

Enterovirus A71 (EV-A71) infection is known to cause hand-foot-mouth disease, which may develop severe symptoms such as encephalitis, herpangina, and paralysis, leading to pulmonary edema and even death in children under five years old. Existing animal models for EV-A71 pathogenesis have limitations, necessitating novel models to study human-relevant disease mechanisms. Using glycoproteomic profiling to identify EV-A71-interacting proteins, we previously discovered human nucleolin (hNCL) as an attachment molecule that enhances viral binding and infection in vitro. Here, we developed human nucleolin transgenic (hNCL-Tg) mice to investigate EV-A71 pathogenesis in vivo. Compared to wild-type (WT) mice, EV-A71-infected hNCL-Tg mice exhibited higher clinical scores, progressive limb paralysis, and increased mortality. Six days post-infection, hNCL-Tg mice showed elevated viral loads in the spinal cord and skeletal muscle, with pronounced EV-A71 VP1 expression in these tissues and the brainstem. Histopathology revealed severe skeletal muscle damage and significant pulmonary edema, characterized by lung congestion, hemorrhage, and erythrocyte infiltration into alveoli. Infected hNCL-Tg mice also displayed elevated levels of encephalitis- and pulmonary edema-associated proinflammatory cytokines (IL-1β, IL-6, IL-13). These findings establish the hNCL-Tg mouse as a robust model for studying EV-A71 pathogenesis and evaluating preclinical therapeutics.

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