Amino acid variation at VP1-145 of Enterovirus A71 determines the viral infectivity and receptor usage in a primary human intestinal model
Creators
- 1. Viroclinics Xplore., Schaijk, the Netherlands
- 2. Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, the Netherlands
- 3. Tytgat Institute for Intestinal and Liver Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- 4. Department of Epidemiology, Bioinformatics and Animal Models, Wageningen Bioveterinary Research, Wageningen University, Wageningen, The Netherlands
- 5. Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Infectious Diseases, Amsterdam, the Netherlands
Description
Enterovirus A71 (EV-A71) can elicit a wide variety of human diseases such as hand, foot, and mouth disease and severe or fatal neurological complications. It is not clearly understood what determines the neurotropism of EV-A71. It has been observed that amino acid changes in the receptor binding protein, VP1, resulting in viral binding to heparan sulfate proteoglycans (HSPGs) may be important for the ability of EV-A71 to infect neuronal tissue. In this study, we identified that the presence of glutamine, as opposed to glutamic acid, at VP1-145 is key for viral infection in a 2D human fetal intestinal model, consistent with previous findings in an airway organoid model. Moreover, pre-treatment of EV-A71 particles with low molecular weight heparin to block HSPG-binding significantly reduced infectivity of two clinical EV-A71 isolates and viral mutants carrying glutamine at VP1-145. Our data indicates that mutations in VP1 leading to HSPG-binding enhances viral replication in the human gut. These mutations potentially change the cell tropism of EV-A71 which could lead to increased production of viral particles with subsequent neuroinfections.
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1045587_Manuscript.PDF
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