The immune system is primed to sense invading pathogens and knock them dead. Yet bacteria have to make a living, too. They’ve evolved to evade the immune system as best as they can.
A new study led by Igor Brodsky, an assistant professor of pathobiology at the School of Veterinary Medicine, reveals how some salmonella bacteria hide from the immune system, allowing them to persist and cause a systemic infection.
The paper, published in the Journal of Experimental Medicine, looks at a component of the innate immune response called the inflammasome, a complex of proteins that triggers the release of signaling molecules that recruit other elements of the immune system to fight off the pathogen.
“We hypothesized that during the systemic phase of disease, salmonella would have some way of avoiding inflammasome activation,” Brodsky says.
To discern the bacteria’s strategy, Brodsky’s team screened a variety of mutated strains of salmonella. They found that when the gene that encodes the enzyme aconitase was mutated, the inflammasome known as NLRP3 was highly activated, leading researchers to wonder whether the normal version of aconitase might do the opposite, inhibiting the inflammasome.
Aconitase, which converts citrate to isocitrate, is a key component in the metabolic process known as the citric acid or Krebs cycle. This cycle is used by all oxygen-breathing organisms to convert sugar into energy and to produce important molecules for cell growth.
Probing deeper, the team found that mutating two other components of the citric acid cycle—the enzymes isocitrate dehydrogenase and isocitrate lyase—also led to higher activation of the NLRP3 inflammasome. Moreover, when the researchers infected mice with a strain of salmonella that had a mutated version of aconitase, the rodents were able to clear the infection, likely due to the inflammasome being activated.
Brodsky says that their results point to the possibility that the immune system may activate the inflammasome in response to the presence of citrate or some byproduct of citrate.
“Our work fits into this emerging idea that bacterial metabolites might be recognized by various components of the immune system for the purpose of either negatively or positively regulating immune responses,” Brodsky says.
Along with colleagues, Brodsky is currently working to help develop a chicken vaccine, possibly using an aconitase mutant, that could provide the animals with protection against systemic salmonella infection.
“We get salmonella from chickens that are chronically infected,” Brosky says, “so if you could prevent or limit chronic infection of chickens, that would be a nice way to limit salmonella in the food supply.”