MHC class II as novel receptor for influenza A viruses

This research explores alternative receptor usage by influenza A viruses, inspired by the discovery of novel bat-derived strains that do not rely on the canonical sialic acid receptor. We identified major histocompatibility complex (MHC) class II molecules as entry receptors for these bat influenza viruses, revealing a previously unrecognized infection pathway^{1, 2}. Expanding on this finding, we demonstrated that certain human and avian H2 subtype viruses exhibit dual receptor specificity, enabling entry either through MHC class II molecules or via the classical sialic acid route³. This flexibility suggests that influenza viruses may possess a greater capacity for host adaptation than previously appreciated. Notably, the ability of avian viruses to utilize MHC class II molecules from multiple species points to a potential mechanism facilitating cross-species transmission, with direct implications for zoonotic risk assessment.

Ongoing work aims to define the molecular and cellular requirements of this alternative entry pathway. Using CRISPR/Cas9 screens and targeted mutational analyses of the viral hemagglutinin, we are dissecting the determinants of MHC class II–mediated entry and comparing them to the conventional pathway. These efforts seek to clarify the role of dual receptor usage in influenza virus evolution and its contribution to zoonotic potential.

References:

1. Karakus U, et al. MHC class II proteins mediate cross-species entry of bat influenza viruses. Nature 567, 109-112 (2019).
2. Karakus U, Pohl MO, Stertz S. Breaking the Convention: Sialoglycan Variants, Coreceptors, and Alternative Receptors for Influenza A Virus Entry. J Virol 94,  (2020).
3. Karakus U, et al. MHC class II proteins mediate sialic acid independent entry of human and avian H2N2 influenza A viruses. Nat Microbiol 9, 2626-2641 (2024).

Figure from: Stertz S, Karakus U (2025) A new path to spillover: MHC-II entry of influenza A viruses. PLoS Biol