| Autor: |
Chooi WH; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Winanto; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.; National University of Singapore, Faculty of Science (Department of Biological Science), Singapore., Zeng Y; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Lee CY; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Lim ZQ; Infectious Diseases Translational Research Programme (IDTRP); Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Immunology Programme, Life Science Institute, National University of Singapore, Singapore., Gautam P; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Chu JJH; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.; Infectious Diseases Translational Research Programme (IDTRP); Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Loh YH; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Alonso S; Infectious Diseases Translational Research Programme (IDTRP); Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Immunology Programme, Life Science Institute, National University of Singapore, Singapore., Ng SY; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; National Neuroscience Institute, Singapore. |
| Abstrakt: |
Enterovirus A71 (EV-A71) causes Hand, Foot, and Mouth Disease and has been clinically associated with neurological complications. However, there is a lack of relevant models to elucidate the neuropathology of EV-A71 and its mechanism, as the current models mainly utilize animal models or immortalized cell lines. In this study, we established a human motor neuron model for EV-A71 infection. Single cell transcriptomics of a mixed neuronal population reveal higher viral RNA load in motor neurons, suggesting higher infectivity and replication of EV-A71 in motor neurons. The elevated RNA load in motor neurons correlates with the downregulation of ferritin-encoding genes. Subsequent analysis confirms that neurons infected with EV-A71 undergo ferroptosis, as evidenced by increased levels of labile Fe 2+ and peroxidated lipids. Notably, the Fe 2+ chelator Deferoxamine improves mitochondrial function and promotes survival of motor neurons by 40% after EV-A71 infection. These findings deepen understanding of the molecular pathogenesis of EV-A71 infection, providing insights which suggest that improving mitochondrial respiration and inhibition of ferroptosis can mitigate the impact of EV-A71 infection in the central nervous system. |
