Peter Reuther
(Institute of Virology, University Medical Centre of Freiburg, Germany)
The discovery of influenza A virus (IAV) subtypes H17N10 and H18N11 in New World bats challenged the paradigm that viral entry depends on hemagglutinin (HA) binding to sialic acid. Instead, these bat IAV use the protein receptor MHC class II (MHCII). MHCII from diverse species, including humans, mediates infection, and conserved residues within MHCII are critical for interaction with H18. Here, we structurally characterized the MHCII binding site on H18.
We purified soluble H18 homotrimers and MHCII heterodimers and demonstrated direct interaction by bio-layer interferometry. Soluble MHCII efficiently blocked H18N11 infection, confirming its essential role in entry. Using hydrogen-deuterium exchange mass spectrometry and cryo-EM, we mapped the MHCII binding interface to a discrete region in the H18 head domain, distinct from the classical sialic acid binding site. Mutational analysis identified key residues required for membrane fusion triggered by the H18-MHCII interaction. Viruses carrying mutations in this interface showed severely impaired growth. Passaging of the mutant viruses led to a compensatory mutation near the binding site that restored membrane fusion and viral replication to wildtype levels.
These findings provide the first structural insights into the H18–MHCII interface and identify critical residues mediating this interaction.
| Registration ID |
INF26- 31
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| Professional status of the speaker |
Senior Scientist
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| Junior scientist status |
No, I am not a junior scientist.
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Jonathan Robert
(Institute of Virology, University Medical Centre of Freiburg, Germany)
Maria K. Osman
(Institute of Virology, University Medical Centre of Freiburg, Germany)
Nico J. Halwe
(Institut für Virusdiagnostik (IVD), Friedrich-Loeffler-Institut, Greifswald - Insel Riems, Germany)
Valeria Calvaresi
(Department of Biochemistry, University of Oxford, UK)
Anna Kotanska
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Jan Gradon
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Leon Michalski
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Stanley Sau
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Stephen Martin
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Eamonn Reading
(Department of Chemistry, Britannia House, King’s College London, London, UK)
Martin Beer
(Institut für Virusdiagnostik (IVD), Friedrich-Loeffler-Institut, Greifswald - Insel Riems, Germany)
John J. Skehel
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Steve J. Gamblin
(Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, UK)
Martin Schwemmle
(Institute of Virology, University Medical Centre of Freiburg, Germany)
Kevin Cimninski
(Institute of Virology, University Medical Centre of Freiburg, Germany)
Antoni G. Wrobel
(Department of Biochemistry, University of Oxford, UK)
Peter Reuther
(Institute of Virology, University Medical Centre of Freiburg, Germany)
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