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Title: Mouse saliva inhibits transit of influenza virus to the lower respiratory tract by efficiently blocking influenza virus neuraminidase activity
Authors: Gilbertson, B
Ng, W.C 
Crawford, S
McKimm-Breschkin, J.L
Brown, L.E
Keywords: membrane protein
sialidase inhibitor
viral protein
virus sialidase
NA protein, influenza A virus
viral protein
amino acid sequence
animal experiment
animal model
antiviral susceptibility
controlled study
enzyme active site
enzyme activity
enzyme inhibition
enzyme substrate
human cell
in vitro study
Influenza A virus (H3N2)
Influenza virus
lower respiratory tract
priority journal
reverse genetics
virus hybrid
virus inhibition
virus resistance
virus strain
antagonists and inhibitors
disease model
innate immunity
MDCK cell line
orthomyxovirus infection
respiratory system
Disease Models, Animal
Immunity, Innate
Influenza A Virus, H3N2 Subtype
Madin Darby Canine Kidney Cells
Orthomyxoviridae Infections
Respiratory System
Reverse Genetics
Viral Proteins
Issue Date: 2017
Publisher: American Society for Microbiology
Citation: Gilbertson, B, Ng, W.C, Crawford, S, McKimm-Breschkin, J.L, Brown, L.E (2017). Mouse saliva inhibits transit of influenza virus to the lower respiratory tract by efficiently blocking influenza virus neuraminidase activity. Journal of Virology 91 (14) : e00145-17. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: We previously identified a novel inhibitor of influenza virus in mouse saliva that halts the progression of susceptible viruses from the upper to the lower respiratory tract of mice in vivo and neutralizes viral infectivity in MDCK cells. Here, we investigated the viral target of the salivary inhibitor by using reverse genetics to create hybrid viruses with some surface proteins derived from an inhibitor-sensitive strain and others from an inhibitor-resistant strain. These viruses demonstrated that the origin of the viral neuraminidase (NA), but not the hemagglutinin or matrix protein, was the determinant of susceptibility to the inhibitor. Comparison of the NA sequences of a panel of H3N2 viruses with differing sensitivities to the salivary inhibitor revealed that surface residues 368 to 370 (N2 numbering) outside the active site played a key role in resistance. Resistant viruses contained an EDS motif at this location, and mutation to either EES or KDS, found in highly susceptible strains, significantly increased in vitro susceptibility to the inhibitor and reduced the ability of the virus to progress to the lungs when the viral inoculum was initially confined to the upper respiratory tract. In the presence of saliva, viral strains with a susceptible NA could not be efficiently released from the surfaces of infected MDCK cells and had reduced enzymatic activity based on their ability to cleave substrate in vitro. This work indicates that the mouse has evolved an innate inhibitor similar in function, though not in mechanism, to what humans have created synthetically as an antiviral drug for influenza virus. © 2017 American Society for Microbiology.
Source Title: Journal of Virology
ISSN: 0022538X
DOI: 10.1128/JVI.00145-17
Rights: Attribution 4.0 International
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