| Title: |
Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence |
| Authors: |
Sun, Liang; Tijsma, Aloys; Mirabelli, Carmen; Baggen, Jim; Wahedi, Maryam; Franco, David; De Palma, Armando; Leyssen, Pieter; Verbeken, Erik; van Kuppeveld, Frank J M; Neyts, Johan; Thibaut, Hendrik Jan; LS Virologie; dI&I I&I-1 |
| Publication Year: |
2019 |
| Subject Terms: |
enterovirus A71; SCID; mouse model; CNS; tropism; pathogenesis; receptor |
| Description: |
Enterovirus A71 (EV-A71) is one of the main causative agents of hand-foot-and-mouth disease and is occasionally associated with severe neurological complications. EV-A71 pathophysiology is poorly understood due to the lack of small animal models that robustly support viral replication in relevant organs/tissues. Here, we show that adult severe combined immune-deficient (SCID) mice can serve as an EV-A71 infection model to study neurotropic determinants and viral tropism. Mice inoculated intraperitoneally with an EV-A71 clinical isolate had an initial infection of the lung compartment, followed by neuroinvasion and infection of (motor)neurons, resulting in slowly progressing paralysis of the limbs. We identified a substitution (V135I) in the capsid protein VP2 as a key requirement for neurotropism. This substitution was also present in a mouse-adapted variant, obtained by passaging the clinical isolate in the brain of one-day-old mice, and induced exclusive neuropathology and rapid paralysis, confirming its role in neurotropism. Finally, we showed that this residue enhances the capacity of EV-A71 to use mouse PSGL1 for viral entry. Our data reveal that EV-A71 initially disseminates to the lung and identify viral and host determinants that define the neurotropic character of EV-A71, pointing to a hitherto understudied role of PSGL1 in EV-A71 tropism and neuropathology. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
2222-1751 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/385050 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/385050 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.5E95136C |
| Database: |
BASE |