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Salmonella Irons out a Tough World

Molecular trickery and the ability to persist within host cells are familiar means by which Salmonella has gained its reputation as a hardy human pathogen. But its hardiness comes from yet another dimension, namely a special means to withstand high levels of iron that it sometimes encounters in the world outside the mammalian gut, according to Howard Hughes Medical Institute investigator Eduardo Groisman and his colleagues at Washington University School of Medicine in St. Louis, Mo. They described recent insights into this newly recognized iron-defense system of Salmonella enterica serovar Typhimurium in the 29 September 2000 issue of the journal Cell.

The capacity of this bacterium to respond to externally encountered iron depends in part on its regulatory system, known as PmrA/PmrB, according to Groisman. "We are very excited about the discovery of the first regulatory system that responds to extracytoplasmic iron and of novel mechanisms of iron-mediated killing," he says. This particular regulatory system detects potentially adverse environmental changes, and responds to them by activating or repressing the expression of various bacterial genes.

"We knew that PmrA/PmrB controlled resistance to polymyxin B," says Groisman. Because domains in the sensing segment of PmrB resemble those found in several mammalian and yeast proteins that bind iron, the investigators speculated that the PmrB protein also can respond to iron. Follow-up tests indeed indicate that iron binds to a portion of PmrB that pokes from the outer membrane into the periplasm of the bacterial cell. The binding of iron to this PmrB domain turns on genes activated by the PmrA member of the A/B tandem.

The response is specific for ferric iron, Fe³⁺. Thus, ferrous iron (Fe²⁺), which is found inside cells, does not serve as an activator, nor do other cations. For the PmrA/PmrB sensory system to protect against high levels of external ferric ions, it must be intact and properly functioning, according to Groisman. For example, among mutants in which one or both of these proteins is structurally or functionally incomplete, ferric ions either inhibit growth or outright kill such cells.

"It was quite a surprise that the PmrA/PmrB system responds to high iron concentrations because all the textbooks tell you that it is low iron that promotes expression of bacterial genes," says Groisman. The response to low levels of iron is considered part of a bacterial cell's effort to maintain sufficient internal iron concentrations for essential processes. "Fe³⁺ is physiologically relevant, although not necessarily during infection of mammalian hosts," he says. "Salmonella experiences high Fe³⁺ levels in soil and groundwater. High levels of Fe³⁺ are present in the stomach after eating and could be another environment where Salmonella experiences Fe³⁺."

Persistence of Salmonella in the soil could be further aided by polymyxin-mediated resistance of PmrA/PmrB. "Polymyxin is produced by the soil bacterium Paeniacillus polymyxa. Furthermore, the (mediated system) is also present in a number of gram-negative species which are not pathogenic, suggesting Fe3+-sensing occurs in non-host environments," says Groisman.

"This research is unique in that it identified a high iron induction," says Brett Finlay of the University of British Columbia. Asked whether the high iron response might affect the pathogenicity of this microorganism, he says, "It is puzzling, as high iron should not normally be encountered within the host." However, the iron response may affect survival of this bacterium either in its mammalian host or elsewhere, he adds. "It is possible another, physiologically relevant signal actually controls activity in vivo, or that we don't understand when Salmonella might encounter high levels within the host."

Why Fe³⁺ is lethal to Salmonella, and exactly how the PmrA/PmrB system protects the cells against its lethal effects are not fully understood. "Our working hypothesis is that [PmrA/PmrB] modifies the lipopolysaccharide that covers the surface of gram-negative bacteria so that iron does not bind to them," Groisman says. "The PmrA/PmrB system also controls expression of proteins mediating modification of LPS that render it less negatively charged, which could then result in a lower affinity of Fe³⁺ for the negatively charged LPS."

Brian Hoyle