tetano
Editor, Senior Moderator
J Virol. 2017 Apr 26. pii: JVI.00145-17. doi: 10.1128/JVI.00145-17. [Epub ahead of print]
[h=1]Mouse saliva inhibits transit of influenza virus to the lower respiratory tract by efficiently blocking influenza neuraminidase activity.[/h] Gilbertson B[SUP]1[/SUP], Ng WC[SUP]1[/SUP], Crawford S[SUP]2[/SUP], McKimm-Breschkin JL[SUP]1[/SUP], Brown LE[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] We have 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 proteins, was the determinant of susceptibility to the inhibitor. Comparison of the NA sequence of a panel of H3N2 viruses with differing sensitivities to the salivary inhibitor revealed that surface residues 368-370 (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 surface 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 mechanism to what man has created synthetically as an antiviral drug for influenza.IMPORTANCE Despite widespread use of experimental pulmonary infection of the laboratory mouse to study influenza infection and pathogenesis, to our knowledge mice do not naturally succumb to influenza. Here we show that mice produce their own natural form of neuraminidase inhibitor in saliva that stops virus from reaching the lungs, providing a possible mechanism for why this species may not experience severe influenza infection in the wild. We show that the murine salivary inhibitor targets the outer surface of the influenza neuraminidase, possibly occluding entry to the enzymatic site rather than binding within the active site like commercially available neuraminidase inhibitors. This knowledge sheds light on how the natural inhibitors of particular species combat infection.
Copyright ? 2017 Gilbertson et al.
PMID: 28446666 DOI: 10.1128/JVI.00145-17
[h=1]Mouse saliva inhibits transit of influenza virus to the lower respiratory tract by efficiently blocking influenza neuraminidase activity.[/h] Gilbertson B[SUP]1[/SUP], Ng WC[SUP]1[/SUP], Crawford S[SUP]2[/SUP], McKimm-Breschkin JL[SUP]1[/SUP], Brown LE[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] We have 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 proteins, was the determinant of susceptibility to the inhibitor. Comparison of the NA sequence of a panel of H3N2 viruses with differing sensitivities to the salivary inhibitor revealed that surface residues 368-370 (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 surface 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 mechanism to what man has created synthetically as an antiviral drug for influenza.IMPORTANCE Despite widespread use of experimental pulmonary infection of the laboratory mouse to study influenza infection and pathogenesis, to our knowledge mice do not naturally succumb to influenza. Here we show that mice produce their own natural form of neuraminidase inhibitor in saliva that stops virus from reaching the lungs, providing a possible mechanism for why this species may not experience severe influenza infection in the wild. We show that the murine salivary inhibitor targets the outer surface of the influenza neuraminidase, possibly occluding entry to the enzymatic site rather than binding within the active site like commercially available neuraminidase inhibitors. This knowledge sheds light on how the natural inhibitors of particular species combat infection.
Copyright ? 2017 Gilbertson et al.
PMID: 28446666 DOI: 10.1128/JVI.00145-17