Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence

Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence

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 or...

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Bibliographic Details
Main Authors: Liang Sun, Aloys Tijsma, Carmen Mirabelli, Jim Baggen, Maryam Wahedi, David Franco, Armando De Palma, Pieter Leyssen, Erik Verbeken, Frank J. M. van Kuppeveld, Johan Neyts, Hendrik Jan Thibaut
Format: Article
Language:English
Published: Taylor & Francis Group 2019-01-01
Series:Emerging Microbes and Infections
Subjects:
Enterovirus A71
SCID
mouse model
CNS
tropism
pathogenesis
Online Access:https://www.tandfonline.com/doi/10.1080/22221751.2019.1644142
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Summary: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.
ISSN:2222-1751

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