Dissection of the molecular mechanisms leading to amyloid arthropathy in chickens
Amyloid arthropathy (AA) in chickens is a disease caused by bacterial infection, predominantly with Enterococcus faecalis (E. faecalis). It has an impact on animal welfare, contributes to the overuse of antibiotics, and results in significant economic losses for the laying hen industry. Amyloid depositions, mainly consisting of aggregated Serum amyloid A (SAA) protein, in large joints of affected animals are characteristic for the disease. The exact mechanism of amyloid deposition in joints of affected chickens is still unknown. The disease mostly affects brown egg laying chickens (BL) whereas white egg laying chickens (WL) are resistant to AA. It is currently thought that a differential immune response is the reason for the difference in the clinical manifestation of AA in BL and WL. We discovered a missense variant (rs739601959) with an in exon 4 of the SAA gene, which is fixed in WL and leads to a predicted amino acid exchange of arginine (R) to serine (S) at position 90 in the full length SAA protein (SAA.R90S). Surprisingly, when overexpressed in chicken hepatocellular carcinoma cells, SAA.R90S was expressed at a higher rate and secreted to a greater degree than the wild-type SAA protein. Moreover, RNASeq analysis showed that the R90S mutant exerted a differential effect on the expression of core transcription factors linked to cell fate determination and cell differentiation. Comparative analysis of gene expression in murine CD4 T-cells stimulated with IL-6/SAA, suggests that SAA.R90S might block an induced cell fate change towards pro-inflammatory T helper 17 cells, which are required for immunological protection against pathogenic bacteria during an acute phase response. Our results provide first mechanistic insights into the genetic resistance of WL to AA and could be applied to commercial layer breeding programs to improve animal welfare and reduce the negative effects of the overuse of antibiotics.
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