Abstract
Viral diseases pose major threats to humans and other animals, including the billions of chickens that are an important food source as well as a public health concern due to zoonotic pathogens. Unlike humans and other typical mammals, the major histocompatibility complex (MHC) of chickens can confer decisive resistance or susceptibility to many viral diseases. An iconic example is Marek's disease, caused by an oncogenic herpesvirus with over 100 genes. Classical MHC class I and class II molecules present antigenic peptides to T lymphocytes, and it has been hard to understand how such MHC molecules could be involved in susceptibility to Marek's disease, given the potential number of peptides from over 100 genes. We used a new in vitro infection system and immunopeptidomics to determine peptide motifs for the 2 class II molecules expressed by the MHC haplotype B2, which is known to confer resistance to Marek's disease. Surprisingly, we found that the vast majority of viral peptide epitopes presented by chicken class II molecules arise from only 4 viral genes, nearly all having the peptide motif for BL2*02, the dominantly expressed class II molecule in chickens. We expressed BL2*02 linked to several Marek's disease virus (MDV) peptides and determined one X-ray crystal structure, showing how a single small amino acid in the binding site causes a crinkle in the peptide, leading to a core binding peptide of 10 amino acids, compared to the 9 amino acids in all other reported class II molecules. The limited number of potential T cell epitopes from such a complex virus can explain the differential MHC-determined resistance to MDV, but raises questions of mechanism and opportunities for vaccine targets in this important food species, as well as providing a basis for understanding class II molecules in other species including humans.
Highlights
The ongoing global pandemic of a coronavirus among humans highlights the enormous challenge of viral disease and the importance of the appropriate immune responses [1,2,3]
Thin horizontal line indicates Marek’s disease virus (MDV) genome of roughly 180 kB, with relevant MDV genes indicated by black boxes labeled with the number of the gene and with arrowheads indicating class II-bound peptides, above the line for genes and peptides oriented from left to right and below the line for right to left
Each vertical stack of arrowheads indicates a single T cell epitope with multiple peptide species, each arrowhead colored according to the number of experimental samples in which the peptide species was found. (C) MDV peptides with decamer motifs were expressed with BL2 02 molecules from insect cells, and the expressed peptide-major histocompatibility complex (MHC) molecules had high thermal stability
Summary
The ongoing global pandemic of a coronavirus among humans highlights the enormous challenge of viral disease and the importance of the appropriate immune responses [1,2,3]. The MHC of humans and typical mammals is an enormous and complex genetic region encoding a wide variety of molecules, with multigene families encoding class I and class II molecules leading to strong genetic associations with autoimmune disease but relatively weak associations with infectious diseases [4]. In contrast to humans and other typical mammals, the level of resistance to many infectious pathogens in chickens can be strongly determined by the MHC (that is, the BF-BL region of the B locus), at least in part because the chicken MHC is much simpler, with single dominantly expressed class I and class II loci [6,7]. Despite enormous efforts in biosecurity, vaccination, and genetic breeding, condemnation and slaughter of huge numbers of infected chickens are relatively frequent [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
