Abstract
Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature.
Highlights
Salmonella enterica serovar Typhimurium is a foodborne bacterial pathogen whose pathology in Man ranges from gastroenteritis to systemic disease [1]
In S. typhimurium and other bacteria intracellular concentrations of c-di-GMP are controlled through multiple GG(D/E)EF domain proteins acting as di-guanylate cyclases (DGCs) and EAL domain proteins acting as c-di-GMP specific phosphodiesterases (PDEs) [8,9,10]
The rdar morphotype is expressed outside the host at ambient temperature, we could recently show that high c-di-GMP levels inhibit the virulence properties invasion and induction of the pro-inflammatory cytokine IL-8 through expression of the biofilm regulator CsgD and/or the extracellular matrix components cellulose and the capsule at body temperature [15] suggesting that c-di-GMP regulates the transition between biofilm formation and virulence at the intestinal epithelial cell lining
Summary
Salmonella enterica serovar Typhimurium is a foodborne bacterial pathogen whose pathology in Man ranges from gastroenteritis to systemic disease [1]. This lifestyle of S. typhimurium requires adaptation and survival mechanisms inside and outside the host. At least eight of the 20 GG(D/E)EF/EAL domain proteins in S. typhimurium contribute directly or indirectly to the regulation of the rdar morphotype, a biofilm phenotype characterized by the expression of the extracellular matrix components cellulose and curli fimbriae [11,12,13]. The rdar morphotype is expressed outside the host at ambient temperature, we could recently show that high c-di-GMP levels inhibit the virulence properties invasion and induction of the pro-inflammatory cytokine IL-8 through expression of the biofilm regulator CsgD and/or the extracellular matrix components cellulose and the capsule at body temperature [15] suggesting that c-di-GMP regulates the transition between biofilm formation and virulence at the intestinal epithelial cell lining
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