Enterovirus D68 Infection in Human Primary Airway and Brain Organoids: No Additional Role for Heparan Sulfate Binding for Neurotropism.

Autor:	Sridhar A; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands., Depla JA; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands.; uniQure Biopharma B.V., Amsterdam, The Netherlands., Mulder LA; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands., Karelehto E; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands., Brouwer L; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands., Kruiswijk L; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands., Vieira de Sá R; uniQure Biopharma B.V., Amsterdam, The Netherlands., Meijer A; National Institute for Public Health and Environment, Centre for Infectious Diseases Research and Laboratory Surveillance, Bilthoven, The Netherlands., Evers MM; uniQure Biopharma B.V., Amsterdam, The Netherlands., van Kuppeveld FJM; Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht Universitygrid.5477.1, Utrecht, The Netherlands., Pajkrt D; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.; Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Emma Children's Hospital Department of Pediatric Infectious Diseases, Amsterdam, The Netherlands., Wolthers KC; Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Department of Medical Microbiology, OrganoVIR Labs, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2022 Oct 26; Vol. 10 (5), pp. e0169422. Date of Electronic Publication: 2022 Sep 26.
DOI:	10.1128/spectrum.01694-22
Abstrakt:	Enterovirus D68 (EV-D68) is an RNA virus that can cause outbreaks of acute flaccid paralysis (AFP), a polio-like disease. Before 2010, EV-D68 was a rare pathogen associated with mild respiratory symptoms, but the recent EV-D68 related increase in severe respiratory illness and outbreaks of AFP is not yet understood. An explanation for the rise in severe disease is that it may be due to changes in the viral genome resulting in neurotropism. In this regard, in addition to sialic acid, binding to heparan sulfate proteoglycans (HSPGs) has been identified as a feature for viral entry of some EV-D68 strains in cell lines. Studies in human primary organotypic cultures that recapitulate human physiology will address the relevance of these HSPG-binding mutations for EV-D68 infection in vivo. Therefore, in this work, we studied the replication and neurotropism of previously determined sialic acid-dependent and HSPG-dependent strains using primary human airway epithelial (HAE) cultures and induced human pluripotent stem cell (iPSC)-derived brain organoids. All three strains (B2/2042, B2/947, and A1/1348) used in this study infected HAE cultures and human brain organoids (shown for the first time). Receptor-blocking experiments in both cultures confirm that B2/2042 infection is solely dependent on sialic acid, while B2/947 and A1/1348 (HSPG to a lesser extent) binds to sialic acid and HSPG for cell entry. Our data suggest that HSPG-binding can be used by EV-D68 for entry in human physiological models but offers no advantage for EV-D68 infection of brain cells. IMPORTANCE Recent outbreaks of enterovirus D68, a nonpolio enterovirus, is associated with a serious neurological condition in young children, acute flaccid myelitis (AFM). As there is no antiviral treatment or vaccine available for EV-D68 it is important to better understand how EV-D68 causes AFM and why only recent outbreaks are associated with AFM. We investigated if a change in receptor usage of EV-D68 increases the virulence of EV-D68 in the airway or the central nervous system and thus could explain the increase in AFM cases. We studied this using physiologically relevant human airway epithelium and cerebral organoid cultures that are physiologically relevant human models. Our data suggest that heparan sulfate proteoglycans can be used by EV-D68 as an additional entry receptor in human physiological models but offers no advantage for EV-D68 infection of brain cells, and our data show the potential of these 46 innovative models for virology.
Databáze:	MEDLINE
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