A wriggly debate

Two very similar studies investigating a single gene's role in pathogen susceptibility have come to pretty much opposite conclusions. A __C. elegans__ gene that was previously shown to affect innate immunity might simply alter the worm's behavior, according to a new linkurl:study;https://www.sciencemag.org/cgi/content/abstract/323/5912/382 published today (Jan. 15) in __Science,__ although some scientists remain skeptical of the paper's findings. Last September, a team led by linkurl:Alejandro Aballay,;https://mgm.duke.edu/faculty/aballay/ a geneticist at the Duke University Medical Center, published a report in Science showing that the __C. elegans__ gene __npr-1__ -- a G protein-coupled receptor (GPCR) that is known to affect oxygen sensation -- controls behavior as well as the worm's innate immune responses in sensory neurons. But now, linkurl:Dennis Kim;https://web.mit.edu/biology/www/facultyareas/facresearch/kim.html of the Massachusetts Institute of Technology, together with Princeton University's linkurl:Leonid Kruglyak,;https://www.eeb.princeton.edu/faculty/Kruglyak/Kruglyak.html report that __npr-1__ confers its pathogen fighting abilities solely by helping worms wriggle away from noxious bacteria, rather than through innate immunity. "We think that behavior is not just necessary but seemingly sufficient" to explain __npr-1__-related differences in pathogen susceptibility, Kim told __The Scientist__. Aballay, however, is not convinced by the new report. "They have issues with some of our interpretations; I have issues with some of their experiments," he told __The Scientist__. The two research teams stumbled upon __npr-1__'s role in bacterial defense independently of one another: Aballay's team discovered the gene by screening dozens of GPCR mutants exposed to the bacterium __Pseudomonas aeruginosa__, while Kim's team noticed a naturally occurring difference in susceptibility to the same pathogen, which they then mapped to __npr-1__, a gene previously implicated in oxygen sensitivity. Both teams then showed that worms with low __npr-1__ expression levels had the highest lethality rates because they tended to aggregate in regions of rich bacterial growth where oxygen levels were lowest. Both teams then did similar experiments -- including investigating other oxygen-sensing mutants, assays at low oxygen concentrations, and growing worms on uniform bacterial lawns -- and came to contradictory conclusions. Kim's team found that behavioral responses alone could explain the differences in __npr-1__ expression and pathogen susceptibility, while Aballay's team implicated immune effects, too. "Behavioral responses cannot account for all the differences we see," said Aballay. "I believe that it was unfair for them to say that their results contradict our conclusions," he added, noting that although Kim's team did not find statistically significant differences in their assays, their results revealed non-significant trends that were consistent with his study's findings. He suggested that using greater sample sizes could resolve the issue. Kim dismisses this criticism as beside the point. "We're talking about small differences, so it's hard to rule out [innate immune effects] either way, but by far the major effect is behavioral," he said. Other researchers, however, think that neither of the two studies is definitive. "I think that [Kim's team] came out much too strongly," said linkurl:Mario de Bono,;https://www2.mrc-lmb.cam.ac.uk/groups/debono/ a geneticist at the UK Medical Research Council's Laboratory of Molecular Biology, who was not involved in either study. "They've shown that behavior is important, but they haven't shown that it's to the exclusion of other [processes]." linkurl:Ricardo Azevedo,;https://wwworm.biology.uh.edu/ an evolutionary geneticist at the University of Houston, who was not involved in the research, agreed. "They sort of argue against [innate immunity] but without addressing the original data," he said. Kim's team examined five transcription factors involved in immune signaling to rule out a role for innate immunity, but these were not the same genes found by Aballay's team to be regulated by both __npr-1__ and the innate immune pathway, Azevedo noted. What's more, Aballay's team used RNA interference of a key immune pathway gene and found a difference between __npr-1__ mutants and wild-type worms, which could not be explained by behavioral differences alone, he added. Aballay also pointed to other evidence from his study in favor of innate immunity. His team performed a genome-wide microarray on wild-type and __npr-1__ mutant worms and found many differentially expressed innate immunity genes. His team also tested two other pathogens -- including __Salmonella enterica__, a bug that does not elicit worm avoidance behavior -- and found that the pathogen susceptibility difference still held. Azevedo is still not completely convinced by either interpretation, but he's keeping an open mind. "There's not the strongest evidence for innate immunity, but it's not just something you can ignore," he said. "I was not convinced by the [Kim's] paper's case that innate immunity was not involved." de Bono echoed this sentiment. "If I were to bet, I would say that there might be something that is non-behaviorally mediated," he said.
**__Related stories:__***linkurl:I smell a... worm;https://www.the-scientist.com/article/display/15670/
[1st August 2005]*linkurl:How worms tackle stress;https://www.the-scientist.com/article/display/22286/
[14th July 2004]*linkurl:Worms, stress, and feeding behavior;https://www.the-scientist.com/article/display/20822/
[31st October 2002]

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