Dopamine Is a Siderophore-Like Iron Chelator That Promotes Salmonella enterica Serovar Typhimurium Virulence in Mice

Abstract

We have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course of Salmonella infections. Dopamine was found to promote the growth of Salmonella both in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected with Salmonella enterica serovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth. Salmonella lacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria. IMPORTANCE Here we show that dopamine increases bacterial iron incorporation and promotes Salmonella Typhimurium growth both in vitro and in vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

Metabolic reprogramming of Salmonella infected macrophages and its modulation by iron availability and the mTOR pathway

“…RNA extraction, cDNA transcription and quantitative RT-PCR was performed exactly as described previously [47]. cDNA levels of the respective genes were calculated as relative expression to the house keeping gene beta-Glucuronidase (Gusbeta).…”

Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3)

“…Low iron diet had an iron content of ≤9 mg iron/kg diet (26), high ion diet contained 5 g iron/kg diet (both diets from Altromin). Male mice were used at 8-12 weeks of age and infected intraperitoneally with 500 CFU of S. Typhimurium in 200 ml PBS (27)(28)(29). After 14 days of infection mice were euthanized by cervical dislocation, spleens and livers were isolated, erythrocytes lysed, and flow cytometry was performed.…”

The Other Obesity Epidemic—Of Drugs and Bugs

“…These biomolecules play a key role in energy metabolism and immune tolerance of gut microbes by upregulating IL-10 ( 77 , 78 ). Interestingly, microbial DA and NE were demonstrated to influence iron absorption and metabolism by functioning as siderophores or bacterial iron scavengers ( 79 , 80 ). Interestingly, a recent study found that enterobactin, an Escherichia coli siderophore, can be transferred to the host, revealing a novel form of inter-kingdom communication ( 81 ).…”