Epigenetic regulation of host defense peptide synthesis

Host defense peptides (HDP) are an integral part of the first line of defense against infections. Modulation of HDP synthesis has emerged as a promising host-directed approach to fight against infections. We have identified several classes of epigenetic compounds capable of inducing HDP gene expression. The objective of this study is to explore a possible synergy in HDP induction among different classes of epigenetic compounds as an antibiotic-free approach to infectious disease control and prevention. Chicken macrophage cell lines and peripheral blood mononuclear cells were treated with or without structurally distinct histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), or DNA methyltransferase inhibitors (DNMTi) individually or in combinations, followed by analysis of the expression levels of HDP and cytokine genes as well as the major genes invovled in barrier function. We found that a combination of HDACi and HMTi or HDACi and DNMTi showed a strong synergy to induce the expression of multiple HDP genes. Tight-junction proteins such as claudin 1 were also synergistically induced by HDACi and HMTi, whereas LPS-induced IL-1β gene expression was suppressed. Overall, we conclude that HDP genes are regulated by epigenetic modifications. Strategies to increase histone acetylation while reducing DNA or histone methylation exert a synergistic effect on HDP induction and, therefore, have potential for the control and prevention of infectious diseases without relying on antibiotics.

Key Words: host defense, innate immunity, epigenetics, antibiotic alternatives, poultry.

Presented at the 10th Symposium on Gut Health in Production of Food Animals 2022, St. Louis, USA.