Edwardsiella ictaluri T3SS Effector EseN Modulates Expression of Host Genes Involved in the Immune Response

Abstract

The type III secretion system (T3SS) effector EseN is encoded on the <i>Edwardsiella ictaluri</i> chromosome and is homologous to a family of T3SS effector proteins with phosphothreonine lyase activity. Previously we demonstrated that <i>E. ictaluri</i> invasion activates extracellular signal-regulated kinases 1 and 2 (ERK1/2) early in the infection, which are subsequently inactivated by EseN. Comparative transcriptomic analysis showed a total of 753 significant differentially expressed genes in head-kidney-derived macrophages (HKDM) infected with an EseN mutant (∆EseN) compared to HKDM infected with wild-type (WT) strains. This data strongly indicates classical activation of macrophages (the M1 phenotype) in response to <i>E. ictaluri</i> infection and a significant role for EseN in the manipulation of this process. Our data also indicates that <i>E. ictaluri</i> EseN is involved in the modulation of pathways involved in the immune response to infection and expression of several transcription factors, including NF-κβ (c-<i>rel</i> and <i>relB</i>), <i>creb3L4</i>, <i>socs6</i> and <i>foxo3a</i>. Regulation of transcription factors leads to regulation of proinflammatory interleukins (IL-8, IL-12a, IL-15, IL-6) and cyclooxygenase-2 (COX-2) expression. Inhibition of COX-2 mRNA by WT <i>E. ictaluri</i> leads to decreased production of prostaglandin E2 (PGE2), which is the product of COX-2 activity. Collectively, our results indicate that <i>E. ictaluri</i> EseN is an important player in the modulation of host immune responses to <i>E.ictaluri</i> infection.