Epigenetic Modification of TLRs in Leukocytes Is Associated with Increased Susceptibility to Salmonella enteritidis in Chickens

Abstract

Toll-like receptors (TLRs) signaling pathways are the first lines in defense against Salmonella enteritidis ( S. enteritidis ) infection but the molecular mechanism underlying susceptibility to S. enteritidis infection in chicken remains unclear. SPF chickens injected with S. enteritidis were partitioned into two groups, one consisted of those from Salmonella-susceptible chickens (died within 5 d after injection, n = 6), the other consisted of six Salmonella-resistant chickens that survived for 15 d after injection. The present study shows that the bacterial load in susceptible chickens was significantly higher than that in resistant chickens and TLR4 , TLR2-1 and TLR21 expression was strongly diminished in the leukocytes of susceptible chickens compared with those of resistant chickens. The induction of expression of pro-inflammatory cytokine genes, IL-6 and IFN-β , was greatly enhanced in the resistant but not in susceptible chickens. Contrasting with the reduced expression of TLR genes, those of the zinc finger protein 493 ( ZNF493 ) gene and Toll-interacting protein ( TOLLIP ) gene were enhanced in the susceptible chickens. Finally, the expression of TLR4 in peripheral blood mononuclear cells (PBMCs) infected in vitro with S. enteritidis increased significantly as a result of treatment with 5-Aza-2-deoxycytidine (5-Aza-dc) while either 5-Aza-dc or trichostatin A was effective in up-regulating the expression of TLR21 and TLR2-1 . DNA methylation, in the predicted promoter region of TLR4 and TLR21 genes, and an exonic CpG island of the TLR2-1 gene was significantly higher in the susceptible chickens than in resistant chickens. Taken together, the results demonstrate that ZNF493 -related epigenetic modification in leukocytes probably accounts for increased susceptibility to S. enteritidis in chickens by diminishing the expression and response of TLR4 , TLR21 and TLR2-1 .

Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis

“…Consistent with the present findings, DNA methylation of the TLR2-1 gene is higher in susceptible chickens infected with Salmonella enteritidis. 23 Moreover, malaria-induced epigenetic fine-tuning of TLR6 and TLR1 through DNA methylation of their gene promoters is important for the initial recognition and final outcome of P. chabaudi infection. 14 A trend towards DNA hyper-methylation of CpG sites of the TLR2 promoter is demonstrated in chronic periodontitis patients.…”

Induction of avian β-defensins by CpG oligodeoxynucleotides and proinflammatory cytokines in hen vaginal cells in vitro

“…1b). These two TLRs play important roles in the defense against Salmonella infection because susceptibility to Salmonella enteritidis is closely related to the responsiveness of three TLRs, namely, TLR4, TLR21, and TLR2 type 1 (Gou et al 2012). It is likely that the upregulation of IL1B and IL6 expression by LPS is caused by an interaction of LPS…”

Genome-Wide Epigenetic Studies in Chicken: A Review

“…Toll-like receptor 4 (TLR4), an immunity-related gene, was found both differentially methylated and expressed between the Fayoumi and Leghorn lines [78]. A previous study has revealed that a susceptible chicken line had a greater methylation level of the TLR4 gene after infection [81] underlining the important role of this gene in the immune response. Thus, this study also highlighted the potential regulatory role of DNA methylation in the control of gene expression.…”