Hemagglutinin Stability Regulates H1N1 Influenza Virus Replication and Pathogenicity in Mice by Modulating Type I Interferon Responses in Dendritic Cells.
Animals
Cell Line
Chemokines
/ metabolism
Cytokines
/ metabolism
Dendritic Cells
/ metabolism
Female
Hemagglutinin Glycoproteins, Influenza Virus
/ genetics
Hemagglutinins
/ genetics
Humans
Hydrogen-Ion Concentration
Influenza A Virus, H1N1 Subtype
/ genetics
Influenza Vaccines
Influenza, Human
/ virology
Interferon Type I
/ metabolism
Lung
/ pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Orthomyxoviridae Infections
/ virology
Protein Stability
Viral Fusion Proteins
Virulence
Virus Replication
/ physiology
hemagglutinin (HA)
influenza virus
interferon responses
mouse model
pathogenesis
protein stability
viral fusion protein
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
17 01 2020
17 01 2020
Historique:
received:
21
08
2019
accepted:
03
11
2019
pubmed:
7
11
2019
medline:
24
7
2020
entrez:
8
11
2019
Statut:
epublish
Résumé
Hemagglutinin (HA) stability, or the pH at which HA is activated to cause membrane fusion, has been associated with the replication, pathogenicity, transmissibility, and interspecies adaptation of influenza A viruses. Here, we investigated the mechanisms by which a destabilizing HA mutation, Y17H (activation pH, 6.0), attenuates virus replication and pathogenicity in DBA/2 mice compared to wild-type (WT) virus (activation pH, 5.5). The extracellular lung pH was measured to be near neutral (pH 6.9 to 7.5). WT and Y17H viruses had similar environmental stability at pH 7.0; thus, extracellular inactivation was unlikely to attenuate the Y17H virus. The Y17H virus had accelerated replication kinetics in MDCK, A549, and RAW 264.7 cells when inoculated at a multiplicity of infection (MOI) of 3 PFU/cell. The destabilizing mutation also increased early infectivity and type I interferon (IFN) responses in mouse bone marrow-derived dendritic cells (DCs). In contrast, the HA-Y17H mutation reduced virus replication in murine airway murine nasal epithelial cell and murine tracheal epithelial cell cultures and attenuated virus replication, virus spread, the severity of infection, and cellular infiltration in the lungs of mice. Normalizing virus infection and weight loss in mice by inoculating them with Y17H virus at a dose 500-fold higher than that of WT virus revealed that the destabilized mutant virus triggered the upregulation of more host genes and increased type I IFN responses and cytokine expression in DBA/2 mouse lungs. Overall, HA destabilization decreased virulence in mice by boosting early infection in DCs, resulting in the greater activation of antiviral responses, including the type I IFN response. These studies reveal that HA stability may regulate pathogenicity by modulating IFN responses.
Identifiants
pubmed: 31694942
pii: JVI.01423-19
doi: 10.1128/JVI.01423-19
pmc: PMC7000976
pii:
doi:
Substances chimiques
Chemokines
0
Cytokines
0
Hemagglutinin Glycoproteins, Influenza Virus
0
Hemagglutinins
0
Influenza Vaccines
0
Interferon Type I
0
Viral Fusion Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : HHSN266200700005C
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201400006C
Pays : United States
Informations de copyright
Copyright © 2020 American Society for Microbiology.
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