Defining the molecular interaction between influenza hemagglutinin and MHC-II

We just posted to bioRxiv a new study led by Bernadeta Dadonaite that uses a novel combination of deep mutational scanning and cryo-EM to show how influenza HA interacts with MHC-II. Many important questions remain about how this interaction evolves and its biological role, and determining its structural basis is a first step towards answering those questions.

Influenza hemagglutinin (HA) has long been known to use sialic acid as a receptor, but about 7 years ago it was shown that some highly diverged bat influenza HAs use MHC-II as their entry receptor. Subsequently it was shown some H2 and H3 HAs could also use MHC-II. However, the structural basis of this interaction has remained unclear.

We first showed that many H5 HAs can bind to avian MHC-II, and then used pseudovirus deep mutational scanning to measure how all mutations to a H5 HA affect entry and binding to tufted duck MHC-II. This work enabled us to functionally define a surface on the HA head that binds MHC-II. We then used identification of mutations that increase HA binding to tufted duck MHC-II to solve a cryo-EM structure of the complex. We also measured how MHC-II mutations affect the interaction.

Our preprint also has lots of other interesting findings related to HA's ability to interact with MHC-II and how this varies across HAs of many subtypes and MHC-II alleles.

In addition to reading the preprint, for more details see:

• This Bluesky thread, which can be read more easily in threaded form here.
• This X thread

To access and view the data, see the following links: https://dms-vep.org/Flu-H5N1-American-Wigeon-2021-HA-tufted-duck-MHCII-DMS/.