Polymorphisms in IRF3 exon 1 influence the immune response to Brucella infection in small ruminants.

Abstract

Brucellosis in small ruminants is primarily caused by Brucella ovis and zoonotic B. melitensis. IRF3 is a key transcription factor for IFNα/β gene induction in response to intracellular pathogens. Previously, we identified a genetic association between the rs540 deletion (a-allele) in IRF3 exon 1 and an increased resistance to B. melitensis natural infection in goats. Here, we studied the effect of IRF3 exon 1 polymorphisms on monocyte-derived macrophages (MDMs) in vitro response to Brucella spp. infection, and on the humoral response of goats to Brucella vaccination. Caprine MDMs with the Aa-genotype for rs540 exhibited higher bacterial load (p < 0.01), decreased production of reactive oxygen species (p < 0.05) and lower induction of iNOS, IL-12b, IL-18 and IL-1α mRNA expression (p < 0.05) at 24 h post-infection (h p.i.) with B. melitensis 16 M, in comparison to the aa-genotype. Moreover, the A-allele was associated with an early negativization to Brucella Buffered Plate Antigen test (p < 0.05) and reduced IgG antibody responses (p < 0.05) after Brucella vaccination in goats. On the other hand, ovine MDMs with the T-T-allele for the haplotype rs853-rs301 in IRF3 exon 1 exhibited lower bacterial loads and intracellular bacteria survival rates (ISR) at 24 h p.i. with B. melitensis Rev. 1 and B. ovis PA (p < 0.05), and reduced production of reactive nitrogen species and anion superoxide at 48 h p.i. with B. ovis (p < 0.001). In summary, these results show that polymorphisms in IRF3 exon 1 can influence the immune response of small ruminants to Brucella infection.