Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature
| Autor: | Isabelle Piuz, Johan Geiser, Manel Essaidi-Laziosi, Laurent Kaiser, Francisco J. Pérez-Rodriguez, Caroline Tapparel, Karl-Heinz Krause, Song Huang, Dominique Garcin, Samuel Constant, Léna Royston |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonology viruses Respiratory System Cultured tumor cells Artificial Gene Amplification and Extension ddc:616.07 Polymerase Chain Reaction Viral Packaging Medicine and Health Sciences lcsh:QH301-705.5 Enterovirus Neurons ddc:616 Intestines/virology Microbial Mutation Temperature Phenotype 3. Good health Cell biology Intestines Capsid Proteins/genetics/metabolism Capsid Cell lines Biological cultures Research Article lcsh:Immunologic diseases. Allergy Immunology Virulence Enterovirus/classification/physiology Biology Microbiology 03 medical and health sciences Extraction techniques Enterovirus Infections/genetics/metabolism/virology Virology Enterovirus Infections Genetics Humans HeLa cells Molecular Biology Techniques Molecular Biology Gene Tropism Innate immune system Neurons/virology Biology and Life Sciences Acids/chemistry Cell cultures Viral Replication RNA extraction Research and analysis methods Viral Tropism 030104 developmental biology lcsh:Biology (General) Viral replication Respiratory System/virology Respiratory Infections Tissue tropism Capsid Proteins Parasitology lcsh:RC581-607 Acids |
| Zdroj: | PLOS Pathogens, Vol. 14, No 4 (2018) P. e1006962 PLoS Pathogens PLoS Pathogens, Vol 14, Iss 4, p e1006962 (2018) |
| ISSN: | 1553-7366 |
| Popis: | Despite their genetic similarities, enteric and respiratory enteroviruses (EVs) have highly heterogeneous biophysical properties and cause a vast diversity of human pathologies. In vitro differences include acid sensitivity, optimal growth temperature and tissue tropism, which reflect a preferential in vivo replication in the respiratory or gastrointestinal tract and are thus key determinants of EV virulence. To investigate the underlying cause of these differences, we generated chimeras at the capsid-level between EV-D68 (a respiratory EV) and EV-D94 (an enteric EV). Although some chimeras were nonfunctional, EV-D94 with both the capsid and 2A protease or the capsid only of EV-D68 were both viable. Using this latter construct, we performed several functional assays, which indicated that capsid proteins determine acid sensitivity and tropism in cell lines and in respiratory, intestinal and neural tissues. Additionally, capsid genes were shown to also participate in determining the optimal growth temperature, since EV-D94 temperature adaptation relied on single mutations in VP1, while constructs with EV-D68 capsid could not adapt to higher temperatures. Finally, we demonstrate that EV-D68 maintains residual binding-capacity after acid-treatment despite a loss of infectivity. In contrast, non-structural rather than capsid proteins modulate the innate immune response in tissues. These unique biophysical insights expose another layer in the phenotypic diversity of one of world’s most prevalent pathogens and could aid target selection for vaccine or antiviral development. Author summary Enteroviruses (EV) are one of the most frequent human pathogens worldwide, causing a broad spectrum of diseases, ranging from the common cold to fatal flaccid paralysis. Surprisingly, this vast phenotypic diversity is not reflected at the genetic level, where despite intensive research, the factors contributing to these variations remain poorly understood. By generating novel chimeric viruses derived from a respiratory (EV-D68) and an enteric (EV-D94) EV, we highlight the crucial role of capsid proteins in acid sensitivity, in vitro tropism and optimal growth temperature. We also show that while capsid proteins are central to the biophysical viability of EV, they elicit only minor effects on the innate immune response. This work identifies key players in the pathogenesis of these highly prevalent viruses, which not only improves our understanding of their biology, but may also better guide the selection of new targets for vaccine and antiviral innovations. |
| Databáze: | OpenAIRE |
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