H19 influenza A virus exhibits species-specific MHC class II receptor usage

Umut Karakus*, Ignacio Mena, Jithesh Kottur, Sara S El Zahed, Rocío Seoane, Soner Yildiz, Leanne Chen, Magdalena Plancarte, LeAnn Lindsay, Rebecca Halpin, Timothy B Stockwell, David E Wentworth, Geert-Jan Boons, Florian Krammer, Silke Stertz, Walter Boyce, Robert P de Vries, Aneel K Aggarwal, Adolfo García-Sastre*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Avian influenza A virus (IAV) surveillance in Northern California, USA, revealed unique IAV hemagglutinin (HA) genome sequences in cloacal swabs from lesser scaups. We found two closely related HA sequences in the same duck species in 2010 and 2013. Phylogenetic analyses suggest that both sequences belong to the recently discovered H19 subtype, which thus far has remained uncharacterized. We demonstrate that H19 does not bind the canonical IAV receptor sialic acid (Sia). Instead, H19 binds to the major histocompatibility complex class II (MHC class II), which facilitates viral entry. Unlike the broad MHC class II specificity of H17 and H18 from bat IAV, H19 exhibits a species-specific MHC class II usage that suggests a limited host range and zoonotic potential. Using cell lines overexpressing MHC class II, we rescued recombinant H19 IAV. We solved the H19 crystal structure and identified residues within the putative Sia receptor binding site (RBS) that impede Sia-dependent entry.

Original languageEnglish
Pages (from-to)1089-1102.e10
JournalCell Host & Microbe
Issue number7
Early online date13 Jun 2024
Publication statusPublished - 10 Jul 2024


  • HA structure
  • MHC class II
  • avian influenza virus surveillance
  • entry receptor
  • glycan array
  • hemagglutinin subtype H19
  • host range
  • influenza A virus
  • receptor binding site
  • recombinant H19 influenza A virus


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