Defining the molecular interaction between influenza hemagglutinin and MHC-II

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Influenza virus hemagglutinin (HA) interaction with major histocompatibility complex class II (MHC-II) is known but poorly understood.
• MHC-II is crucial for adaptive immunity, presenting antigens to T cells.

Purpose of the Study:

• To elucidate the molecular mechanism by which influenza hemagglutinin (HA) interacts with major histocompatibility complex class II (MHC-II) for cell entry.
• To characterize the structural basis of HA-MHC-II binding and identify key residues involved.

Main Methods:

• Pseudovirus deep mutational scanning was employed to assess the impact of mutations in H5 HA on MHC-II binding.
• Cryo-electron microscopy (cryo-EM) was used to determine the structure of the H5 HA-MHC-II complex.
• Mutational analysis of MHC-II was performed to identify critical interaction sites.

Main Results:

• Diverse H5 HAs utilize MHC-II for cell entry, with avian MHC-II facilitating more efficient entry than human MHC-II.
• A high-resolution cryo-EM model revealed the molecular interface between H5 HA and tufted duck MHC-II.
• Mutational data indicated that the MHC-II alpha chain is the primary determinant of interaction, with contributions from the beta chain.

Conclusions:

• Influenza HA-MHC-II interaction is a conserved mechanism across various influenza subtypes (H1, H2, H3, H5, H7, H9).
• Understanding these interactions provides insights into viral entry pathways and host-pathogen dynamics.
• Structural and mutational data offer a foundation for future studies on influenza virus evolution and host adaptation.