Growth hormone interacts with the Marek's disease virus SORF2 protein and is associated with disease resistance in chicken

Abstract

Marek's disease (MD) is a lymphoproliferative disease of chickens induced by a herpesvirus, the MD virus (MDV). Because MD is a significant economic problem to the poultry industry, there is great interest in enhancing genetic resistance, which is controlled by multiple genes. The influence of the MHC has been clearly demonstrated, and several relevant quantitative trait loci have been mapped; however, no single gene influencing MD resistance has been identified. Transcription of SORF2 is perturbed in the MDV recombinant clone RM1 due to a solo insertion of the reticuloendotheliosis virus long terminal repeat, which may explain the loss of oncogenicity for this strain. Hypothesizing that SORF2-interacting host proteins are involved in MD resistance, we screened a chicken splenic cDNA library by the yeast two-hybrid assay using SORF2 as bait. The chicken growth hormone (GH) structural peptide was identified, and the specific interaction was verified by coimmunoprecipitation. Immunohistochemical staining and indirect immunofluorescence assay indicated that GH and SORF2 can be coexpressed in MDV-infected cells both in vitro and in vivo. Furthermore, polymorphism in the GH gene (GH1) is associated with the number of tissues with tumors in commercial White Leghorn chickens with the MHC B*2͞B*15 genotype. We conclude that GH1 may well be a MD resistance gene.

DNMT gene expression and methylome in Marek’s disease resistant and susceptible chickens prior to and following infection by MDV

“…For example, we discovered an iDMR at the promoter of MD resistance candidate gene GH. 24,25 In addition, the enhanced transcription levels of CDC42 were coordinated with an observed decline in DNA methylation in a nearby DMR before and after infection, consistent with the fact that methylation suggest it may contribute to MD susceptibility by deregulation of the cell cycle and proliferation. Pathway analysis reveals that DMRs were enriched in genes involved in inducible nitric oxide synthase (iNOS) signaling, which have been shown to produce nitric oxide (NO) to reduce viral replication.…”

Comparison and contrast of genes and biological pathways responding to Marek’s disease virus infection using allele-specific expression and differential expression in broiler and layer chickens

“…Likewise, IL5R, IL21R of the Cytokine R module, PTPN6 (aka SHP1), and PTPN11 (aka SHP2) are all found at the beginning of the JAK/STAT pathway for broilers and layers. It is also interesting to note that growth hormone ( GH ), one of the three MD resistance genes identified [8], also lies at the start of the JAK/STAT pathway though we could not evaluate for ASE due to the lack of SNPs in the F 1 progeny. Interestingly, nuclear factor-kappa B (NF-κ B), which regulates genes associated with cell survival, proliferation, programmed cell death (PCD), stress, inflammation, and immunity was previously shown to be a key component of MDV infection [26] and showed ASE in the layers in this study as well as being a member of the TLR signaling pathway among others (e.g., viral carcinogenesis, B and T cell receptor signaling, chemokine signaling).…”

“…In the past, focusing on the experimental White Leghorn (layer) lines 6 3 and 7 2 , which are MD resistant and susceptible, respectively, we have utilized multiple techniques such as genome-wide QTL scans [6,7], transcript profiling with microarrays [8], and protein-protein interaction [9] screens to understand the response to MDV infection and MD genetic resistance. Integrating the results from these approaches identified three genes and many other strong candidates that confer genetic resistance to MD [8,10,11]. While promising, these genes account for only a small fraction of the observed genetic variation, a situation that is similar for many other complex traits.…”

Transcriptional Profiling of MEq-Dependent Genes in Marek’s Disease Resistant and Susceptible Inbred Chicken Lines

“…Namely, genome-wide genetic screens (e.g., QTL scans) to identify regions in the chicken genome containing the gene(s) of interest, and functional genomic screens (e.g., transcript profiling or virus-host protein-protein interaction screens) to provide candidate genes (reviewed in 7). Despite identifying three MD resistance genes (growth hormone, SCA2, and MHC class II [8-10] and many more strong candidates, like other complex traits, it has been very difficult to comprehensively identify the remaining genes that are involved in resistance.…”