TY - JOUR
T1 - Amino acid variation at VP1-145 of enterovirus A71 determines the viral infectivity and receptor usage in a primary human intestinal model
AU - Aknouch, Ikrame
AU - García-Rodríguez, Inés
AU - Giugliano, Francesca Paola
AU - Calitz, Carlemi
AU - Koen, Gerrit
AU - van Eijk, Hetty
AU - Johannessson, Nina
AU - Rebers, Sjoerd
AU - Brouwer, Lieke
AU - Muncan, Vanesa
AU - Stittelaar, Koert J.
AU - Pajkrt, Dasja
AU - Wolthers, Katja C.
AU - Sridhar, Adithya
N1 - Funding Information: The authors wish to thank K. Weijer, E. Siteur-van Rijnstra, and A. Voordouw for facilitating the provision of the fetal tissues. We acknowledge Jonneke de Rijck and Guido van der Net and their colleagues of Viroclinics Xplore, Thomas J. Roodsant of Medical Microbiology, Amsterdam UMC, and Jacqueline Vermeulen of Tytgat Institute for their excellent technical support. We wish to thank H. Shimizu and Y. Nishimura (National Institute of Infectious Diseases, Japan) for providing of EV-A71 infectious cDNA clones and E. Duizerand and K. Benschop (National Institute for Public Health and the Environment, the Netherlands) for providing of EV-A71 virus strains. Funding Information: This study was funded by Viroclinics Xplore, and OrganoVIR (grant 812673), and GUTVIBRATIONS (grant 953201). Publisher Copyright: Copyright © 2023 Aknouch, García-Rodríguez, Giugliano, Calitz, Koen, van Eijk, Johannessson, Rebers, Brouwer, Muncan, Stittelaar, Pajkrt, Wolthers and Sridhar.
PY - 2023
Y1 - 2023
N2 - 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 virulence and fitness 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 the 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 resulting in increased production of viral particles at the primary replication site could lead to a higher risk of subsequent neuroinfection. Importance: With the near eradication of polio worldwide, polio-like illness (as is increasingly caused by EV-A71 infections) is of emerging concern. EV-A71 is indeed the most neurotropic enterovirus that poses a major threat globally to public health and specifically in infants and young children. Our findings will contribute to the understanding of the virulence and the pathogenicity of this virus. Further, our data also supports the identification of potential therapeutic targets against severe EV-A71 infection especially among infants and young children. Furthermore, our work highlights the key role of HSPG-binding mutations in the disease outcome of EV-A71. Additionally, EV-A71 is not able to infect the gut (the primary replication site in humans) in traditionally used animal models. Thus, our research highlights the need for human-based models to study human viral infections.
AB - 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 virulence and fitness 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 the 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 resulting in increased production of viral particles at the primary replication site could lead to a higher risk of subsequent neuroinfection. Importance: With the near eradication of polio worldwide, polio-like illness (as is increasingly caused by EV-A71 infections) is of emerging concern. EV-A71 is indeed the most neurotropic enterovirus that poses a major threat globally to public health and specifically in infants and young children. Our findings will contribute to the understanding of the virulence and the pathogenicity of this virus. Further, our data also supports the identification of potential therapeutic targets against severe EV-A71 infection especially among infants and young children. Furthermore, our work highlights the key role of HSPG-binding mutations in the disease outcome of EV-A71. Additionally, EV-A71 is not able to infect the gut (the primary replication site in humans) in traditionally used animal models. Thus, our research highlights the need for human-based models to study human viral infections.
KW - EV-A71
KW - Transwell
KW - VP1-145
KW - heparin sulfate proteoglycan
KW - human inestinal organoids
KW - polarized epithelium
UR - http://www.scopus.com/inward/record.url?scp=85159017541&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fmicb.2023.1045587
DO - https://doi.org/10.3389/fmicb.2023.1045587
M3 - Article
C2 - 37138595
SN - 1664-302X
VL - 14
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
M1 - 1045587
ER -