Systems Analysis of Immune Responses in Marek's Disease Virus-Infected Chickens Identifies a Gene Involved in Susceptibility and Highlights a Possible Novel Pathogenicity Mechanism

Abstract

Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus that causes disease that is both a cancer model and a continuing threat to the world's poultry industry. This comprehensive gene expression study analyzes the host response to infection in both resistant and susceptible lines of chickens and inherent expression differences between the two lines following the infection of the host. A novel pathogenicity mechanism, involving the downregulation of genes containing HIC1 transcription factor binding sites as early as 4 days postinfection, was suggested from this analysis. HIC1 drives antitumor mechanisms, suggesting that MDV infection switches off genes involved in antitumor regulation several days before the expression of the MDV oncogene meq. The comparison of the gene expression data to previous QTL data identified several genes as candidates for involvement in resistance to MD. One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Understanding which genes are involved in susceptibility/resistance to MD and defining the pathological mechanisms of the disease gives us a much greater ability to try to reduce the incidence of this virus, which is costly to the poultry industry in terms of both animal welfare and economics.

Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite

“…Irg1 expression has been detected in the lung tissue of mice during the early phase of influenza A virus infection (77) and in chickens infected with Marek's disease (87). Given the enzymatic function of CAD/IRG1 to produce the antimicrobial compound itaconic acid, it is intriguing that its expression can also be induced during viral infections, since viruses do not possess a proper metabolism toward which itaconic acid could potentially interfere.…”

Genomic Variation between Genetic Lines of White Leghorns Differed in Resistance to Marek’s Disease

“…Yet MD continues to cost the poultry industry, with an estimated revenue of over one billion dollars each year worldwide, which are incurred by the routine prevention measures and condemnation, and remains a serious threat to the poultry industry since commercial lines of chickens at large are susceptible to MD and new isolates of MD viruses (MDV) have been emerging with escalated virulence [6][7][8][9][10][11][12]. Therefore, current control measures using commercially available vaccines in the same routine as has been practiced during the last half century could be overwhelmed at an…”

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

“…Increased Irg1 expression levels have also been detected in chicken spleen macrophages after infection with Salmonella enterica (10). Furthermore, it has been shown that IRG1 could play an important role in the susceptibility toward Marek disease virus (11). Irg1 was originally identified as a 2.3-kb cDNA from a library synthesized from mRNA isolated from a murine macrophage cell line after LPS stimulation (12).…”