For years scientists have puzzled over why the intracellular pathogen Salmonella is able to survive — and thrive — in human and animal tissues, even within otherwise hostile cells that are part of the body’s immune system, such as white blood cells known as macrophages.

While multiple factors enable Salmonella to adapt to harsh conditions experienced during infection, a new Yale study reveals the molecular basis for the metabolic adaptations this pathogen undergoes that promotes its survival.

Writing in the journal Proceedings of the National Academy of Sciences, a team of Yale researchers identify the process — including the role of a key signaling molecule that helps regulate carbon uptake in these organisms — that underlies the physiological changes governing Salmonella’s carbon source preference during infection.

Their findings also show that the behavioral changes commonly observed in Salmonella in laboratory settings don’t necessarily reflect how they behave in the natural environment, said Eduardo A. Groisman, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis at the Yale School of Medicine and senior author of the study.

They also offer new insights into the role of metabolism in antibiotic tolerance, the researchers say.

“We know that Salmonella exhibits an increased tolerance to antibiotics when it is inside of macrophages,” said Nick Pokorzynski, a postdoctoral associate in Groisman’s lab and lead author of the study. “But a longstanding dilemma has been that while you can determine how sensitive Salmonella is to a given antibiotic in the laboratory — where Salmonella can appear sensitive [to that antibiotic] — when you try to treat the infection with the same antibiotic, it is no longer effective.

“These findings support a growing body of literature that implicates metabolism as a major foundation for antibiotic tolerance in bacteria,” he said.

Bacteria, like all living organisms, rely on some form of carbon for most cellular processes — and their preferred or available diet plays a key role in their metabolism and physiology. Decades of research has shown that most microorganisms prefer glucose, a simple sugar, over other carbon sources.

The same is true for Salmonella enterica serovar Typhimurium, a common form of Salmonella — at least when it is grown in laboratory media. But when found inside macrophages, Yale researchers say, Salmonella’s so-called “carbon preference” becomes upended, showing instead a preference for alternative sources of carbon, such as gluconate and glycerol. This difference, researchers say, is likely the result of the host cell “starving” the pathogen of magnesium, an essential cofactor in hundreds of chemical reactions that fuel multiple cellular functions.

When a mammalian cell detects a pathogen, it responds by withholding magnesium. This forces the pathogen to carefully regulate the amount of magnesium it uses so that the cell doesn’t get the upper hand and eventually eliminate it. In Salmonella, the reduced concentration of magnesium induces changes in metabolism and other important physiological adjustments — including slower growth and increased tolerance to antibiotics.