Study reveals how some bacterial infections become chronic

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"... A new study ... sheds light on the biological mechanisms that enable another kind of Salmonella to evade the immune system and cause long-term infections. The team focused on the “nontyphoidal” forms of Salmonella, which cause food-borne illness and, like the typhoidal form, can linger in the body long after the initial infection. By examining the genomes of bacteria collected from hundreds of people with persistent Salmonella infections, they discovered genetic mutations that both reduce the bacteria’s “virulence,” or ability to infect, and dampen the host’s immune responses, creating a kind of molecular camouflage that shields the bacteria from the immune system’s gaze. This insight could one day lead to new diagnostic approaches or treatments that prevent these infections from becoming chronic.  ...
they found that while most people cleared the infection after a week or so without treatment, roughly 2.2 percent of the cases became persistent infections that lingered for months to years. ...
They confirmed that most of the ​​cases were due to chronic infection by the same strain, rather than reinfection by different strains of the same bacteria. After analyzing the genomes of Salmonella in patient samples at various time points, the team highlighted mutations in two genes, barA and sirA, that arose in the bacteria repeatedly during chronic infection. ...
The mutated genes had different misspellings in different patients, suggesting that the bacteria evolve independently to lower the host immune response. ..."

From the highlights and abstract:

"Highlights

• Salmonella global regulators are frequently mutated during persistent human infection

• The barA/sirA virulence regulatory pathway was most frequently mutated

• barA/sirA mutants were less virulent and elicited a weakened host immune response

• barA/sirA mutants colonized mice and were shed during persistent salmonellosis

Summary

Several bacterial pathogens, including Salmonella enterica, can cause persistent infections in humans by mechanisms that are poorly understood. By comparing genomes of isolates longitudinally collected from 256 prolonged salmonellosis patients, we identified repeated mutations in global regulators, including the barA/sirA two-component regulatory system, across multiple patients and Salmonella serovars. Comparative RNA-seq analysis revealed that distinct mutations in barA/sirA led to diminished expression of Salmonella pathogenicity islands 1 and 4 genes, which are required for Salmonella invasion and enteritis. Moreover, barA/sirA mutants were attenuated in an acute salmonellosis mouse model and induced weaker transcription of host immune responses. In contrast, in a persistent infection mouse model, these mutants exhibited long-term colonization and prolonged shedding. Taken together, these findings suggest that selection of mutations in global virulence regulators facilitates persistent Salmonella infection in humans, by attenuating Salmonella virulence and inducing a weaker host inflammatory response."

Study reveals how some bacterial infections become chronic | Broad Institute Scientists uncover mutations that allow Salmonella to fly under the immune system’s radar for years

Persistent Salmonella infections in humans are associated with mutations in the BarA/SirA regulatory pathway (no public access)

Graphical abstract