The internal ribosome entry site determines the neurotropic potential of enterovirus A71

Guan-Hong Wu; Kuo-Ming Lee; Chia-Yu Kao; Shin-Ru Shih

doi:10.1016/j.micinf.2023.105107

The internal ribosome entry site determines the neurotropic potential of enterovirus A71

Microbes Infect. 2023 Jun;25(5):105107. doi: 10.1016/j.micinf.2023.105107. Epub 2023 Jan 26.

Authors

Guan-Hong Wu¹, Kuo-Ming Lee², Chia-Yu Kao³, Shin-Ru Shih⁴

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan.
² International Master Degree Program for Molecular Medicine in Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan; Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan; Division of Pediatric Infectious Diseases, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333 Taiwan.
³ Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan.
⁴ Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan; Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, 333 Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, And Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 333 Taiwan. Electronic address: srshih@mail.cgu.edu.tw.

PMID: 36708870
DOI: 10.1016/j.micinf.2023.105107

Abstract

The mechanisms underlying tissue-specific replication of enteroviruses are currently unclear. Although enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are both common pathogens that cause hand-foot-mouth disease, they display quite different neurotropic properties. Herein, we characterized the role of the internal ribosome entry site (IRES) in determining neurovirulence using an oral inoculation model of EV-A71. The receptor transgenic (hSCARB2-Tg) mice developed neurological symptoms after being infected with a mouse-adapted EV-A71 strain (MP4) via different administrative routes. Intragastric administration of the MP4 strain caused pathological changes such as neuronal loss and neuropil vacuolation, whereas replacing EV-A71 IRES with CV-A16 abolished the neuropathological phenotypes. The attenuated neurotropic potential of IRES-swapped EV-A71 was observed even in mice that received intraperitoneal and intracerebral inoculations. Fewer chimeric MP4 viral RNAs and proteins were detected in the mouse tissues, regardless of the inoculation route. Tissue-specific replication can be reflected in cell-based characterization. While chimeric MP4 virus replicated poorly in human intestinal C2BBe1 and neuroblastoma SH-SY5Y cells, its replication in susceptible rhabdomyosarcoma cells was not affected. Overall, our results demonstrated that the IRES determined the neurotropic potential of EV-A71 and CV-A16, emphasizing the importance of the IRES in tissue tropism, along with the host receptors.

Keywords: Coxsackievirus A16; Enterovirus A71; Internal ribosome entry site; Intragastric administration; Neurotropism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Viral
Enterovirus A, Human* / genetics
Enterovirus Infections*
Enterovirus* / genetics
Hand, Foot and Mouth Disease*
Humans
Internal Ribosome Entry Sites
Mice
Neuroblastoma*

Substances

Internal Ribosome Entry Sites
Antigens, Viral