Immune cells attack dangerous bacteria by engulfing them and then releasing a cascade of defense molecules. But some bacteria, known as intracellular pathogens, have evolved to survive this onslaught and replicate inside immune cells. The result can be Salmonella poisoning or even tuberculosis. A recent study in Science reveals that these sneaky intracellular bacteria know when to defend themselves, multiply, and cause disease by sensing the very compounds that the attacking immune cell releases. Accumulation of the molecule succinate in particular informs Salmonella enterica serovar Typhimurium that it’s inside an immune cell, explains senior author Roi Avraham, a host–pathogen biologist at the Weizmann Institute of Science, in Rehovot, Israel.
Avraham and coauthors carried out the study in mouse macrophage immune cells. They first infected these cells with Salmonella and measured changes in gene expression that occurred simultaneously in host and pathogen. While the macrophage upregulated certain metabolic genes, the bacteria upregulated genes associated with virulence, in particular building a needle-like secretion system that releases proteins to interfere with host defenses. To understand exactly how the host’s metabolic changes might have affected the bacteria, the researchers next crippled macrophages so they could not change their metabolism to make defensive compounds. Without the hosts’ immunometabolites, the bacteria didn’t build their needle-like secretion systems. “This was a surprise,” Avraham says, “because it was not known that the metabolic changes of the host are sensed in any way by the bacterium.”
Finally, the researchers grew Salmonella bacteria in flasks using nutrients and pH conditions similar to those inside of a host cell. Then the researchers added 10 synthetic immune cell metabolites one-by-one to the flasks, to see which molecules might fool the bacteria into thinking they were inside a host cell. Of all the metabolites, the “secret ingredient” was succinate, Avraham says. “If we use succinate and only succinate, then these bacteria will build the entire secretion system.”
The big question now, says Cammie Lesser, a microbiologist at Massachusetts General Hospital in Boston who wrote an accompanying perspective piece for the recent study, is how exactly the bacteria sense the succinate. Avraham and his team demonstrated that the bacteria took up the succinate with a funnel-like transporter protein. When the team induced mutations to destroy the succinate transporter, the bacteria could no longer divide and replicate in host cells. Finally, when the researchers infected mice with these mutant Salmonella, the animals easily fought off infection.
Immunologist Luke O’Neill, at Trinity College Dublin, in Ireland, finds the results intriguing. “It would be interesting if the authors could somehow target the process they’ve found, possibly to devise a vaccine or therapeutics,” he says.
Indeed, Avraham and coauthors suspect that other intracellular bacteria might sense similar host metabolic changes to cue their infection cycles. Future work will likely test how a range of different bacterial pathogens respond to succinate and other metabolites. Avraham’s research group is also hunting for pharmaceutical candidates that inhibit succinate transport in bacteria. If they do find a drug candidate, it should have minimal side effects, he says, because bacterial succinate transporters are very different from human protein transporters. Unlike a classical antibiotic that kills bacteria, this treatment would not kill the bug but would stop it from replicating and causing infection. Given the immense and worsening problem of antibiotic resistance, Avraham calls anti-infective treatments “one very interesting theme.”
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