Evolutionary pressures rendered by animal husbandry practices for avian influenza viruses to adapt to humans

Abstract

Commercial poultry operations produce and crowd billions of birds every year, which is a source of inexpensive animal protein. Commercial poultry is intensely bred for desirable production traits, and currently presents very low variability at the major histocompatibility complex. This situation dampens the advantages conferred by the MHC's high genetic variability, and crowding generates immunosuppressive stress. We address the proteins of influenza A viruses directly and indirectly involved in host specificities. We discuss how mutants with increased virulence and/or altered host specificity may arise if few class I alleles are the sole selective pressure on avian viruses circulating in immunocompromised poultry. This hypothesis is testable with peptidomics of MHC ligands. Breeding strategies for commercial poultry can easily and inexpensively include high variability of MHC as a trait of interest, to help save billions of dollars as a disease burden caused by influenza and decrease the risk of selecting highly virulent strains.

Keywords: Livestock husbandry; Virology.

Figure 1

Emergence of strains of avian influenza A viruses with new host specificities and increased virulence: possible mechanisms for selection by animal husbandry practices that reduce host genetic diversity and compromise immunity Top panel: mutations may modify specificity of binding sites of HA or NA from á2,3-SA to á2,6-SA directly or indirectly through changes in epistasis between HA and NA, or in NP, M proteins, and polymerases, which affect outcomes of genetic events in IAV. Bottom panel: Mutations affecting cleavability of HA by different proteases affect tissue tropism and thus transmissibility, as well as virulence. The figure was created with MindGraph.

Figure 2

Mechanism for selection by reduced MHC diversity of avian IAV mutants with potential for increased virulence and/or inter-species spillovers A schematic representation of NPs or HAs in two strains of avian IAVs depicts possible peptides (colored forms) for presentation to CTLs within distinct peptide binding grooves (PBGs) encoded by different alleles of chicken BF MHC class I. In a situation of high genetic diversity at BF (depicted in the two columns of birds to the left of Figure 2), CTLs will kill host cells infected with IAV strain X and clear the virus, regardless of the viral NP or HA peptide presented; cells from BF15 birds infected with escape mutant Z are not killed because they are unable to present any NP or HA-derived peptides to CTLs. Mutant Z is thus selected, but circulates in a small number of birds and presents a lower chance for inter-species spillovers (e.g., to humans working at industrial farms) or for mixing if infected birds reach live poultry markets. In a situation of low genetic diversity (the two columns of birds to the right of Figure 2), cells from BF15 birds infected with escape mutant Z will be not killed. As in a situation of high genetic diversity at BF, mutant Z is thus also selected, but it now circulates in a large number of birds, thus presenting a higher chance for inter-species spillovers or for reassortment of viral gene segments and mixing with other birds in live poultry markets. In this example, the following codes and premises apply: peptides of HAs colored in red in strains X and mutant Z contain amino acids located at the protein’s RBS; the RBS of mutant strain Z’s HA presents ability to bind to human SA; mutant strain Z’s red peptide lost the ability to bind to BF15′ PBG; mutant strain Z’s NP or HA proteins do not suffer functional constraints and the selected virus is fit. For clarity, molecular interactions between MHC peptide-binding groves and amino acids of viral HA peptides are simplified and four alleles represent a situation of high genetic diversity and one allele represents a situation of low genetic diversity in two flocks of thousands of birds each. Also, for clarity, the example resorts to mutants at NP’s and HA’s SA-binding RBS, but all mutations that affect viral proteins involved in species-specificities of IAV, e.g., example cleavage sites of HA by different proteases are subject to the same mechanisms of selection. The figure was created with MindGraph