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https://doi.org/10.1128/JVI.00145-17
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 sialidase viral protein amino acid sequence animal experiment animal model antiviral susceptibility Article controlled study enzyme active site enzyme activity enzyme inhibition enzyme substrate human human cell in vitro study Influenza A virus (H3N2) Influenza virus lower respiratory tract mouse nonhuman priority journal reverse genetics saliva virus hybrid virus inhibition virus resistance virus strain animal antagonists and inhibitors disease model dog enzymology genetics immunology innate immunity lung MDCK cell line orthomyxovirus infection respiratory system saliva virology Animals Disease Models, Animal Dogs Immunity, Innate Influenza A Virus, H3N2 Subtype Lung Madin Darby Canine Kidney Cells Mice Neuraminidase Orthomyxoviridae Infections Respiratory System Reverse Genetics Saliva 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. https://doi.org/10.1128/JVI.00145-17 | 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 | URI: | https://scholarbank.nus.edu.sg/handle/10635/179195 | ISSN: | 0022538X | DOI: | 10.1128/JVI.00145-17 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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