Molecular Mechanism Of Bat MHC Ⅰ Ptal-N~*01:01 Presenting Highly Pathogenic Virus-derived Peptides

Bats harbor many zoonotic viruses,including highly pathogenic viruses to humans and other mammals.The infections by these viruses are typically asymptomatic in bats raising questions about immune differences that might exist between bats and other mammals.In particular,the features of bat adaptive immunity are still largely unknown.Though the critical cellular and molecular components of the adaptive immune system are conserved and functional in bats,a large number of unique amino acid substitutions or insertions occur in bat immune genes,including MHC I.In this study,we screened and identified a series of bat MHC I Ptal-N*01:01-binding peptides derived from four different bat-related viruses,i.e.Hendra virus,Ebola virus,MERS-CoV and influenza H17N10 virus.The structures of Ptal-N*01:01 shows unusual peptide presentation features,that the bat-specific sequence combination of the 3AA insertion at the N-terminal of the α1 helix and the charge matching residues at the positions 59/65 enables the tight anchoring the P1-Asp in pocket A of bat MHC I.As the traditional primary anchoring positions,the B and F pockets of Ptal-N*01:01 also shows unconventional conformations,which contribute to unusual peptide motif and distinct peptide presentation compared to other higher mammals.Interestingly,these uncommon peptide presentation features of bat MHC I may be shared by MHC I from different marsupials.Our study provides a benefit recommendation to understand bat adaptive immunity and to the development of vaccines against bat-borne pathogenic viruses in humans.Not only for the host of the virus,but also for the study of human MHC class I molecules presenting virus-derived peptides urged to study deeply.Influenza viruses,such as 2009 pandemic A(HIN 1)influenza virus(2009 pH 1N1)and avian influenza A(H7N9)virus(H7N9),which spread across the species,pose a great threat to human health and cause socioeconomic losses.Since 2009,circulation of 2009 pH1N1 has become a seasonal influenza virus.The sustaining epidemics have resulted in certain T-cell immune level among healthy populations.In comparison to M1 protein of 2009 pHIN1,the H7N9 Ml has 4 segments with clustering substitutions.We defined the cross-reactivity immunity between 2009 pH1N1 and H7N9 and identified four T-cell epitopes.There was a certain level of T-cell immunity to H7N9 in the healthy population,but still weaker than that to 2009 pH1N1.Peptides derived from H7N9 which had mutations induced significant lower T-cell responses.The limited pre-existing T-cell immunity against H7N9 in healthy populations was partially contributed by H7N9 amino acid mutations in novel identified epitopes.Our study on T-cell immunity against influenza viruses provides an important reference for understanding the preexisting immune responses to avian influenza virus,and benefits the development of universal influenza vaccine.In short,we have discovered the unique characteristics of bat MHCI Ptal-N*01:01 in the presentation of virus-derived peptides through structural immunological studies,and it is more prone to marsupials in mammals.Structural immunology is provided to explore the fact that bats carry potent virus but do not cause disease.At the same time,we also screened T cell epitopes from the non-conserved segments of Ml protein in 2009 pH1N1,which provided an important reference for the development of universal vaccines.