NF-KB REGULATION AND SUSCEPTIBILITY TO MENINGOCOCCAL DISEASE

Abstract

Epithelial cells are the first line of defense against pathogens, crucial in sensing microbes and mounting an effective immune response notably through activation of the NF-kB pathway. We characterized genome-wide binding of one NF-kB member, RELA, to five stimuli mimicking infection in human nasopharyngeal epithelial cells. We identified a minority of stimulus-specific sites, especially in response to viral-like Poly I:C stimulus which induced a distinct RELA profile compared to bacterial stimuli. We also investigated changes in H3K27ac, marking activated enhancers and promoters, after stimulation with the bacterial endotoxin lipopolysaccharide. We identified regions of increased deposition, particularly at enhancers and overlapping with RELA binding sites. Finally, we performed targeted sequencing of these regulatory regions identified and genetic association analysis to investigate the risk of non-coding variants in the susceptibility to meningococcal disease, a relevant infectious disease. Several new polymorphisms showed signs of association and potential regulatory effects on pertinent genes.