Influenza Virus with Increased pH of Hemagglutinin Activation Has Improved Replication in Cell Culture but at the Cost of Infectivity in Human Airway Epithelium.
A549 Cells
Animals
Cell Culture Techniques
/ methods
Disease Models, Animal
Dogs
Epithelial Cells
/ cytology
Female
Host-Pathogen Interactions
Humans
Hydrogen-Ion Concentration
Influenza A Virus, H1N1 Subtype
/ pathogenicity
Influenza, Human
/ virology
Madin Darby Canine Kidney Cells
Mice
Neuraminidase
/ chemistry
Point Mutation
Protein Stability
Respiratory System
/ cytology
Single-Cell Analysis
Viral Proteins
/ chemistry
Virus Replication
hemagglutinin
influenza
viral replication
virology
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
01 09 2019
01 09 2019
Historique:
received:
11
01
2019
accepted:
02
06
2019
pubmed:
14
6
2019
medline:
3
6
2020
entrez:
14
6
2019
Statut:
epublish
Résumé
Pandemic H1N1 (pH1N1) influenza virus emerged from swine in 2009 with an adequate capability to infect and transmit between people. In subsequent years, it has circulated as a seasonal virus and evolved further human-adapting mutations. Mutations in the hemagglutinin (HA) stalk that increase pH stability have been associated with human adaptation and airborne transmission of pH1N1 virus. Yet, our understanding of how pH stability impacts virus-host interactions is incomplete. Here, using recombinant viruses with point mutations that alter the pH stability of pH1N1 HA, we found distinct effects on virus phenotypes in different experimental models. Increased pH sensitivity enabled viruses to uncoat in endosomes more efficiently, manifesting as increased replication rate in typical continuous cell cultures under single-cycle conditions. A more acid-labile HA also conferred a small reduction in sensitivity to antiviral therapeutics that act at the pH-sensitive HA fusion step. Conversely, in primary human airway epithelium cultured at the air-liquid interface, increased pH sensitivity attenuated multicycle viral replication by compromising virus survival in the extracellular microenvironment. In a mouse model of influenza pathogenicity, there was an optimum HA activation pH, and viruses with either more- or less-pH-stable HA were less virulent. Opposing pressures inside and outside the host cell that determine pH stability may influence zoonotic potential. The distinct effects that changes in pH stability exert on viral phenotypes underscore the importance of using the most appropriate systems for assessing virus titer and fitness, which has implications for vaccine manufacture, antiviral drug development, and pandemic risk assessment.
Identifiants
pubmed: 31189708
pii: JVI.00058-19
doi: 10.1128/JVI.00058-19
pmc: PMC6694820
pii:
doi:
Substances chimiques
Viral Proteins
0
NA protein, influenza A virus
EC 3.2.1.18
Neuraminidase
EC 3.2.1.18
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200187/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT105736MA
Pays : United Kingdom
Informations de copyright
Copyright © 2019 Singanayagam et al.
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