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The bacterial pathogen Salmonella typhimurium causes intestinal inflammation. S. typhimurium injects effector proteins such as SopD that stimulate a signaling cascade, ultimately leading to inflammation. However, researchers from Yale and Shandong University discovered that SopD is bifunctional and can alternatively stimulate or inhibit inflammation. “It contains the ‘Yin and Yang’ elements of the Salmonella/host interaction within the same protein… a remarkable piece of evolution,” said Jorge Galán, lead researcher of the study and chair of the Department of Microbial Pathogenesis at Yale School of Medicine.
“[Inflammation is] essential for [S. typhimurium] to colonize the intestinal tract, since it allows Salmonella to [compete] with the resident microbiota and secure nutrients that are otherwise not accessible in the uninflamed intestine,” Galán said. Rab8 is a regulatory protein that is central for an anti-inflammatory signaling pathway that helps the host recover homeostasis after inflammation. Therefore, by inhibiting Rab8, SopD stimulates inflammation and helps the pathogen replicate within the intestine.
When the researchers solved the SopD-Rab8 complex’s crystal structure, they identified SopD’s unexpected second function: SopD can activate Rab8 and stimulate an anti-inflammatory response. In other words, opposing enzymatic activities are present within the same protein. Rab8 normally binds to GDI2, an inhibitor that blocks Rab8 activity. However, SopD can displace GDI2 to activate Rab8 and inhibit inflammation. By doing so, S. typhimurium sacrifices virulence to preserve host stability, maximizing its ability to continue replicating.
“[This research is] providing major insight into the pathogenesis of chronic intestinal inflammatory diseases such as Crohn’s disease,” Galán said. Understanding Salmonella has implications in the development of novel therapeutic strategies.
Lian, H., Jiang, K., Tong, M. et al. The Salmonella effector protein SopD targets Rab8 to positively and negatively modulate the inflammatory response. Nat Microbiol (2021). https://doi.org/10.1038/s41564-021-00866-3