Mechanism for Persistent Salmonella enterica serovar Enteritidis Infections in Chickens: Induction of Anti-Inflammatory Host Cell Signaling and the Migration and Activation of T Regulatory T Cells

Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens that is asymptomatic of disease, resulting in a persistent colonization of the ceca.  The underlying mechanisms that control this persistent infection of chickens by Salmonella are unknown.  We hypothesize that a tolerogenic response is induced by alterations of host signaling pathways that mediate the influx and functional activation of CD4+CD25+ T regulatory (Treg) cells.  Here, we evaluated the development of immunological tolerance in chickens infected with S.Enteritidis in a persistent infection model (4-14 days post infection).  For the first time, we outline the induction of a tolerogenic response in the cecum of chickens infected with S. Enteritidis beginning around 4 days post- infection.  The response is induced by a series of phosphorylation-mediated changes in the cecal tissue of chickens during the development of a persistent Salmonella infection.  The tolerance is characterized by alterations in T cell signaling (dephosphorylation of phospholipase c-γ1) and mTOR signaling pathways (increased phosphorylation of AMP-activated protein kinase) and blockage of IFN-γ protection through the disruption of the JAK-STAT signaling pathway (dephosphorylation of JAK2, JAK3, and STAT4).  Further, we found  a reduction in pro-inflammatory cytokine mRNA expression and an increase in anti-inflammatory cytokine mRNA expression.  Lastly, 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.  These studies define a mechanism by which Salmonella infection influences the host responsiveness that establishes a persistent colonization of the avian cecum.