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Title: A role for the non-canonical Wnt-ß-Catenin and TGF-ß signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar Enteritidis persistent cecal infection in chickens

item Kogut, Michael - Mike
item Arsenault, Ryan

Submitted to: Frontiers in Veterinary Infectious Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/10/2015
Publication Date: 9/8/2015
Publication URL:
Citation: Kogut, M.H., Arsenault, R.J. 2015. A role for the non-canonical Wnt-ß-Catenin and TGF-ß signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar Enteritidis persistent cecal infection in chickens. Frontiers in Veterinary Infectious Diseases. 2:1-11.

Interpretive Summary: Baby chicks get infected with Salmonella bacteria early in life and the bacteria are able to survive in the chicks throughout their life. Because of this, Salmonella can be consistently released from the birds and infect the other chicks. Also, the presence of Salmonella in the chicks when they go to market means that they can get into chicken meat products where they can cause food poisoning in humans. The purpose of these experiments is to try to understand how Salmonella can survive in chicks for so long without being "seen" by the chick’s immune system. We found that Salmonella causes a change in the immune response of the baby chicks so that they are "invisible" to the immune system. Thus, the immune cells cannot attack Salmonella and kill it. These results are important to the pharmaceutical industry because we have identified a specific target to stimulate the bird’s immune system and provide protection against infection.

Technical Abstract: Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens. However, the response is short-lived, asymptomatic of disease, resulting in a persistent colonization of the ceca, and fecal shedding of bacteria. The underlying mechanisms that control this persistent infection of chickens by Salmonella are unknown. Recently, we found an expansion of the Treg population and subsequent increased in vitro immunosuppressive functions of the CD4^+CD25^+ cells isolated from the ceca of the Salmonella-infected chickens by day 4 post-infection that increased steadily throughout the course of the 14 days of infection; whereas the number of CD4^+CD25^+ cells in the non-infected controls remained steady throughout the study. CD4^+CD25^+ cells from cecal tonsils of S. enteritidis-infected birds had greater expression of IL-10 mRNA content than the CD4^+CD25^+ cells from the non-infected controls at all the time points studied. These results suggest the development of a tolerogenic immune response in the cecum of Salmonella-infected chickens may lead to the persistance of Salmonella cecal colonization. Using a chicken-specific kinome peptide immune array, we have analyzed the signaling pathways altered during the establishment of this tolerogenic state. This analysis has revealed a role for the non-canonical Wnt signaling pathway in the cecum at 4 days post-infection. Infection induced the significant (p < 0.01) phosphorylation of the G-protein-coupled transmembrane protein, Frizzled 1 (FZD1), which results in an influx of intracellular Ca^++ that leads to the activation (phosphorylation) of the Ca^++-dependent effector molecules calcium/calmodulin-dependent kinase II (CamKII), ß-catenin, protein kinase C (PKC), JUN N-terminal kinase (JNK), and activation of the transcription factor, NFAT. Nuclear translocation of NFAT resulted in a significant increase in the mRNA expression of the anti-inflammatory cytokines IL-10 and TGF-ß. Increased expression of TGF-ß4 mRNA activates the TGF-ß signaling pathway that phosphorylates the receptor-activated Smads, Smad2, and Smad3. Combined with the results from our Treg studies, these studies describe kinome-based phenotypic changes in the cecum of chickens during Salmonella Enteritidis infection starting 4 days post-infection that leads to an anti-inflammatory, tolerogenic local environment, and results in the establishment of persistent intestinal colonization.