Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence. Issue 1 (1st January 2019)

• Record Type: Journal Article
• 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
• Is Part Of: Emerging microbes & infections. Volume 8:Issue 1(2019)
• Page Start: 1076
• Page End: 1085
• Publication Date: 2019-01-01
• Subjects: Enterovirus A71 -- SCID -- mouse model -- CNS -- tropism -- pathogenesis -- receptor; Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1080/22221751.2019.1644142
• Languages: English
• ISSNs: 2222-1751

Abstract

ABSTRACT: 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.