Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Abstract

Recognition of conserved bacterial products by innate immune receptors leads to inflammatory responses that control pathogen spread but that can also result in pathology. Intestinal epithelial cells are exposed to bacterial products and therefore must prevent signaling through innate immune receptors to avoid pathology. However, enteric pathogens are able to stimulate intestinal inflammation. We show here that the enteric pathogen Salmonella Typhimurium can stimulate innate immune responses in cultured epithelial cells by mechanisms that do not involve receptors of the innate immune system. Instead, S. Typhimurium stimulates these responses by delivering through its type III secretion system the bacterial effector proteins SopE, SopE2, and SopB, which in a redundant fashion stimulate Rho-family GTPases leading to the activation of mitogen-activated protein (MAP) kinase and NF-κB signaling. These observations have implications for the understanding of the mechanisms by which Salmonella Typhimurium induces intestinal inflammation as well as other intestinal inflammatory pathologies.

Author Summary

Salmonella Typhimurium is one of the most common causes of food-borne illness in the United States and a major cause of diarrheal diseases in developing countries. This pathogen induces diarrhea by stimulating inflammation in the intestinal tract. This study shows that S. Typhimurium delivers molecules into epithelial cells with the capacity to stimulate the production of pro-inflammatory substances. This mechanism may help the pathogen to initiate the inflammatory response in the intestinal epithelium. This study provides insight into the mechanisms by which Salmonella Typhimurium causes diarrhea.