Structural Definition of Duck Major Histocompatibility Complex Class I Molecules That Might Explain Efficient Cytotoxic T Lymphocyte Immunity to Influenza A Virus

Abstract

A single dominantly expressed allele of major histocompatibility complex class I (MHC I) may be responsible for the duck's high tolerance to highly pathogenic influenza A virus (HP-IAV) compared to the chicken's lower tolerance. In this study, the crystal structures of duck MHC I (Anpl-UAA*01) and duck β2-microglobulin (β2m) with two peptides from the H5N1 strains were determined. Two remarkable features were found to distinguish the Anpl-UAA*01 complex from other known MHC I structures. A disulfide bond formed by Cys95 and Cys112 and connecting the β5 and β6 sheets at the bottom of peptide binding groove (PBG) in Anpl-UAA*01 complex, which can enhance IAV peptide binding, was identified. Moreover, the interface area between duck MHC I and β2m was found to be larger than in other species. In addition, the two IAV peptides that display distinctive conformations in the PBG, B, and F pockets act as the primary anchor sites. Thirty-one IAV peptides were used to verify the peptide binding motif of Anpl-UAA*01, and the results confirmed that the peptide binding motif is similar to that of HLA-A*0201. Based on this motif, approximately 600 peptides from the IAV strains were partially verified as the candidate epitope peptides for Anpl-UAA*01, which is a far greater number than those for chicken BF2*2101 and BF2*0401 molecules. Extensive IAV peptide binding should allow for ducks with this Anpl-UAA*01 haplotype to resist IAV infection.IMPORTANCE Ducks are natural reservoirs of influenza A virus (IAV) and are more resistant to the IAV than chickens. Both ducks and chickens express only one dominant MHC I locus providing resistance to the virus. To investigate how MHC I provides IAV resistance, crystal structures of the dominantly expressed duck MHC class I (pAnpl-UAA*01) with two IAV peptides were determined. A disulfide bond was identified in the peptide binding groove that can facilitate Anpl-UAA*01 binding to IAV peptides. Anpl-UAA*01 has a much wider recognition spectrum of IAV epitope peptides than do chickens. The IAV peptides bound by Anpl-UAA*01 display distinctive conformations that can help induce an extensive cytotoxic T lymphocyte (CTL) response. In addition, the interface area between the duck MHC I and β2m is larger than in other species. These results indicate that HP-IAV resistance in ducks is due to extensive CTL responses induced by MHC I.

A Glimpse of the Peptide Profile Presentation by Xenopus laevis MHC Class I: Crystal Structure of pXela-UAA Reveals a Distinct Peptide-Binding Groove

“…1D). Many of these residues, namely, Y7, Y58, T140, K143, W144, Y158, and Y170, can interact directly by hydrogen bonds or indirectly by participating in hydrogen bond networks with the peptide ligand, which has been extensively reported for other pMHC-I structures (33,36,(42)(43)(44) and is discussed for pXela-UAAg below.…”

“…In addition, because the AB loop and CD loop in the pXela-UAAg a1 domain and the EF loop in the a2 domain have their own features, the AB loop in pXela-UAAg can directly combine with Xela-b2m; the EF loop and CD loop are shorter than those in mammals, causing the CD loop to contain two fewer amino acids and the EF loop to contain one fewer amino acid in nonmammalian structures than in mammalian structures. However, pXela-UAAg is similar to known nonmammalian structures (chickens, ducks, and grass carp) (3,5,36,43). Moreover, four amino acids in Xela-b2m that interact with Xela-UAAg are conserved in mammals and other vertebrates.…”

“…The R83, T140, and K143 residues are well conserved among species, although in mammals, the R83 residue has been replaced by a tyrosine (45), and R/Y83, T140, and K143 can be involved in hydrogen bonding of the peptide ligand P9 residue main chain (32,43). However, among pMHC-I F pockets, some flexibility can be observed; the orientations of the Y/R83, T140, K143, and W144 residues can differ, and they do not always participate in hydrogen bonding of the peptide ligand main chain (3,36,43). In the case of pXela-UAAg, only R83 and T140, but not K143, form hydrogen bonds with the P9 main chain.…”

“…6A, 6B). Moreover, there is one more residue after the 114th amino acid of the PBGs in mammalian structures than in nonmammalian structures (3,36,43) (frog, duck, chicken, and grass carp), resulting in the longer EF loop in mammals than in nonmammals (Fig. 6A).…”

The Drivers of Pathology in Zoonotic Avian Influenza: The Interplay Between Host and Pathogen

“…This limited repertoire may explain why chickens show more severe clinical outcomes due to HPAI such as H5N1 compared to waterfowl, as ducks show extensive diversity in their MHC class I alleles which allows the immune system greater coverage for viral variation ( 165 ). A recent investigation into duck MHC class I molecules found that the duck Anpl -UAA*01 complex showed similar peptide binding properties to HLA-A*02:01 in humans and as such appears to cover a greater array of influenza A virus epitopes compared to similar chicken MHC molecules such as BF2*2101 ( 166 ). Furthermore, migratory shorebirds which act as reservoirs for AI viruses (in particular LPAI H9N2) show increased diversity in their MHC alleles, likely as a mechanism for protecting against foreign pathogens that may be encountered during migration.…”