Immune response feeds parasite

Salmonella is able to out compete resident gut microbes by deriving energy from the immune response that is supposed to combat the pathogen, according to a study published this week in Nature.

Salmonella typhimurium
Image: Wikimedia commons,
Volker Brinkmann, Max Planck Institute
for Infection Biology, Berlin, Germany

"It was a surprise," said microbiologist linkurl:Samuel Miller;http://depts.washington.edu/daid/faculty/miller.htm of the University of Washington, who was not involved in the research. "[Salmonella] is using [the host immune response] to its own advantage." It's an "interesting story," added linkurl:Brett Finlay;http://www.finlaylab.msl.ubc.ca/ of the University of British Columbia, who also did not participate in the study, in an email -- "a real twist on pathogenic mechanisms." Salmonella enterica (specifically, serotype Typhimurium) is a gut parasite known to cause diarrhea and intestinal inflammation. The inflammatory response is part of a multipronged host immune response aimed at eliminating the bacteria, but recent studies have suggested that inflammation does just the opposite -- enhances Salmonella growth and transmission. A team led by microbiologist linkurl:Andreas Bäumler;http://www.ucdmc.ucdavis.edu/medmicro/staff/baumler.html of the University of California, Davis, set out to determine how the bacteria might be taking advantage of the host immune response. One possibility, they thought, had to do with an unusual metabolic pathway in which Salmonella uses a sulfur-based molecule called tetrathionate as a terminal electron acceptor during respiration. Because few other microbes are able to use tetrathionate to respire, researchers often use the compound to identify Salmonella in mixed-species biological samples, such as stool from patients with diarrhea -- culturing samples on tetrathionate-rich growth media increases the growth of Salmonella in proportion to other bacteria present. But scientists hadn't considered this pathway to be relevant when Salmonella infects mammals because tetrathionate was not thought to exist in mammalian hosts. Bäumler's team wondered if there wasn't actually a hidden source of tetrathionate in the gut. Mammalian intestines do, after all, harbor an abundance of thiosulphates, which result when the gut epithelial cells' convert the toxic hydrogen sulfide released by gut bacteria breaking down sulphur-containing foods. And oxidizing thiosulphates is exactly how researchers generate the tetrathionate in the growth media used for detecting Salmonella. Furthermore, the inflammation process initiated by the immune system spawns reactive oxygen species (ROS), which may serve as the perfect oxidizing agents for the conversion. Measuring the formation of tetrathionate in infected mice, the team confirmed their suspicions: They found significant levels of tetrathionate present in the intestines of infected mice, but only in those mice able to launch a normal inflammation response that would generate the ROS needed to oxidize the thiosulfates. To confirm that it was the bacteria's ability to use tetrathionate for respiration that allowed it to benefit from inflammation, the researchers co-cultured wild-type Salmonella with a mutant strain unable to perform tetrathionate respiration. While both strains performed equally well in the presence of oxygen (an alternative electron acceptor for respiration), the wild-type strain outperformed its mutant counterpart when oxygen was low or not present (as in the mammalian gut) and the thiosulfates were oxidized to tetrathionate. The results were confirmed in vivo, where the wild-type strain was markedly higher than the mutant in mouse colons 4 days after infection. "[It's] kind of neat trick," Bäumler said. "Salmonella has these virulence factors to trigger inflammation, and this inflammation is necessary to generate tetrathionate, and tetrathionate is necessary to outgrow [the other bacteria]." "This type of mechanism is beautiful," agreed microbiologist linkurl:Wolf-Dietrich Hardt;https://www1.ethz.ch/microbiol/research/hardt/hardtw of the Institute of Microbiology in Switzerland, who was not involved in the research. "It's exactly what we have been looking for to explain why Salmonella can benefit from an inflamed gut." This is likely not the whole story, however, Hardt added. The competitive advantage demonstrated in this study for wild-type Salmonella over mutants unable to use tetrathionate is probably not enough to compensate for how "normally, if there's no inflammation, Salmonella gets entirely outcompeted by the gut flora," he said. Furthermore, there are other bacteria that benefit from gut inflammation that do not employ tetrathionate respiration, he said. "So I would expect there's going to be additional effects that will have to explain the real benefit for Salmonella." Still, the results speak to the fantastic ingenuity of microbial pathogens, said Miller, who wrote an accompanying News & Views article in Nature. "Not only do pathogens evolve to resist [the host immune responses], but they've evolved to use them to generate more energy." S.E. Winter, "Gut inflammation provides a respiratory electron acceptor for Salmonella," Nature, 467: 426-9. 2010.
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[22nd April 2010]