Abstract ECMIS 2015
ETEC virulencefactors modulate the intestinal immune system
Bert Devriendt
EnterotoxigenicE. coli (ETEC) are still a major cause of postweaningdiarrhea in piglets and result in significant economic losses in swine production industry.In addition, ETEC infections lead to traveller’s diarrhea and intestinal infections in children in less affluent countries.ETEC produce several virulence factors, including fimbriae and enterotoxins, which are associated with pathogenesis. The fimbriae or colonization factors are displayedon the bacterial surface enabling the colonization of the small intestine. In swine, F4 and F18 fimbriae are most frequently associated with ETEC-induced diarrhea. Inaddition, porcine ETEC strains secretethe enterotoxinsLT, STa and STb, which contribute to diarrhea via their action on ion transporters.
However, these virulence factors are not merely involved in ETEC pathogenesis, but also modulate the host intestinal immune system. For instance, the STb enterotoxin is critical for diarrhea induction during early infection in piglets, but also triggers the production of IL-17A mRNA in small intestinal tissues. Surprisingly, this IL-17A mRNA was produced by non-immune cells. BesidesSTb, ETEC-derived fimbriae also seem to have functions that stretch beyond their adhesion function. Previously, we demonstrated that oral delivery of purified F4 fimbriae induces intestinal immune responses, protecting piglets from a challenge ETEC infection. This is quite remarkableas the intestinal immune system daily encounters a vast array of foreign antigens derived from food and gut-residing commensals, resulting in adefault tolerance response to soluble antigens. Both the polymeric nature of the F4 fimbriae and their interaction with transcytoticreceptors at the apical surface of enterocytes are pivotal for this protective mucosal immunity. Recently, we identified aminopeptidase N (APN) as the epithelial receptor involved in the transcytosis of F4 fimbriae. In addition, antibody-mediated targeting to APN also promoted mucosalimmunity in a pig model. As such,bindingto epithelial APN seems necessary to switch the local micro-environment from a tolerogenic to an immune-inductive state and selective antigen targeting to APN could enhance the efficacy of oral vaccines.As opposed to F4 fimbriae, oral immunisation with F18 fimbriae fails to protect animals from a challenge infection. Besidesstructuraldifferencesand a distinctuptakemechanismby the intestinal epithelium, these fimbriaedifferently modulate the function of intestinal phagocytes. Indeed, F18 fimbriae drastically diminished the antigen presentation capacity of small intestinal mononuclear phagocytes. As F18 fimbriae bind glycosphingolipids, they presumably disrupt membrane dynamics, leading to an impaired antigen presentation ability ofthese phagocytes. These results hint at novel immune evasive mechanisms employed by bacterial pathogens.
In conclusion, ETEC virulence factors differently modulate the mucosal immune system and unraveling the underlying mechanisms may provide novel insights in the host pathogen interaction, further accelerating ETEC vaccine design.