Impact of Catecholamines on the Interaction of Salmonella with Intestinal Mucosa

In addition to the finding that pigs subject to social stress or transport exhibit increased faecal excretion of S. enterica serovar Typhimurium (Isaacson et al. 1999; Callaway et al. 2006), several studies have addressed the impact of pre-treating Salmonella or the host with catecholamines on the outcome of infection. Culture of S. Typhimurium in serum-SAPI medium containing 2 mM NE increased colonisation of selected tissues following oral inoculation of piglets compared to bacteria grown in Luria Bertani medium in the absence of NE (Toscano et al. 2007). However, it is likely that the physiological status of bacteria grown in serum-rich minimal salts medium is different to that of bacteria cultured in rich media and, though comparable numbers of bacteria were administered, they may have differed in growth phase and gene expression. Indeed, studies in the author's laboratory failed to reproduce the effect of precultivation in the presence of NE when S. Typhimurium strain 4/74 was grown in LB ± 5 mM NE prior to inoculation of 6-week-old Large White pigs (Stevens MP, unpublished observations).

In relation to the role of stress-related catecholamines during systemic salmonel-losis, it has been reported that NE promotes Salmonella encephalopathy in calves challenged orally with clinical isolates of serovars Enteritidis, Montevideo and Saintpaul associated with neurological disease. Calves given 45 mg/kg NE daily via the intramuscular route developed neurological signs following inoculation with these isolates and had evidence of bacterial replication in the brain, whereas control animals given a placebo were only positive for bacteria by faecal culture (McCuddin et al. 2008). In the same study however, daily intramuscular administration of NE did not enhance faecal excretion of S. Typhimurium DT104 and even decreased excretion of S. Dublin (McCuddin et al. 2008), albeit that the relative ability of NE deposited in muscle to act on bacteria at enteric and systemic sites in calves at this dose is ill-defined. Intra-gastric administration of NE to mice the day before inoculation with S. Typhimurium increased cecal colonisation and translocation to the liver in a dose-dependent manner (Williams et al. 2006). Similarly, chicks given twice daily NE by crop instillation exhibited elevated levels of S. enterica serovar Enteritidis in the ceca and liver compared to controls (Methner et al. 2008).

Research in the author's laboratory has indicated that S. Typhimurium-induced fluid accumulation and 111In-labelled neutrophil recruitment in bovine ligated ileal loops is increased by mixing the bacteria with NE immediately prior to inoculation (Pullinger et al. 2010). However, as with E. coli O157:H7, relatively high concentrations of NE (5 mM) were required to produce a statistically robust phenotype in this model. Using explants of porcine jejunal Peyer's patch mucosa clamped in Ussing chambers, addition of NE to the contraluminal aspect increased uptake of S. Choleraesuis in a phentolamine-sensitive manner (Green et al. 2003). Whilst this implies that NE may facilitate S. Choleraesuis invasion by a mechanism dependent on host adrenergic receptors, NE did not significantly enhance internalisation of S. Typhimurium DT104 by porcine jejunal Peyer's patch explants or ileal non-follicular mucosa in Ussing chambers (Schreiber et al. 2007). Indeed treatment of such explants with sympathomimetic drugs even decreased recoveries of S. Typhimurium DT104 (Brown and Price 2008). S. Typhimurium invades porcine intestinal mucosa more efficiently than S. Choleraesuis in Ussing chambers (Brown and Price 2008) and ileal loops (Paulin et al. 2007), and the effect of exogenous catecholamine on invasion may therefore be less pronounced if a finite level of uptake is possible under the assay conditions. Further studies are required to determine if there are strain- or serovar-specific mechanisms by which catecholamines may modulate the outcome of S. enterica infections.

Studies on the importance of release of catecholamines from endogenous stores on the virulence of Salmonella are lacking. A glucose analogue, 2-deoxy-D-glucose (2DG), previously shown to induce many of the hallmark parameters of physiological stress in pigs (Stabel 1999), failed to reactivate S. Choleraesuis at enteric or systemic sites when given to carrier animals (Stabel and Fedorka-Cray 2004), however catecholamine levels in the intestines or circulation of treated and control animals were not measured. Studies in the author's laboratory have indicated that administration of 40 mg/kg 6-hydroxydopamine intravenously to pigs 8 or 16 days after oral inoculation with S. Typhimurium caused a transient but statistically significant increase in the number of excreted Salmonella relative to infected pigs given diluent (Stevens MP, unpublished observations). This is consistent with the outgrowth of commensal coliforms described in 6-hydroxydopamine treated mice (Lyte and Bailey 1997).

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