Salmonella enterica serovar Typhimurium DeltamsbB Triggers Exacerbated Inflammation in Nod2 Deficient Mice

Claes, Anne-Kathrin, Steck, Natalie, Schultz, Dorothee, Zahringer, Ulrich, Lipinski, Simone, Rosenstiel, Philip, Geddes, Kaoru, Philpott, Dana J., Heine, Holger and Grassl, Guntram A. (2014) Salmonella enterica serovar Typhimurium DeltamsbB Triggers Exacerbated Inflammation in Nod2 Deficient Mice PLoS ONE, 9 (11). e113645-e113645.

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Abstract

The intracellular pathogen Salmonella enterica serovar Typhimurium causes intestinal inflammation characterized by edema, neutrophil influx and increased pro-inflammatory cytokine expression. A major bacterial factor inducing pro-inflammatory host responses is lipopolysaccharide (LPS). S. Typhimurium DeltamsbB possesses a modified lipid A, has reduced virulence in mice, and is being considered as a potential anti-cancer vaccine strain. The lack of a late myristoyl transferase, encoded by MsbB leads to attenuated TLR4 stimulation. However, whether other host receptor pathways are also altered remains unclear. Nod1 and Nod2 are cytosolic pattern recognition receptors recognizing bacterial peptidoglycan. They play important roles in the host's immune response to enteric pathogens and in immune homeostasis. Here, we investigated how deletion of msbB affects Salmonella's interaction with Nod1 and Nod2. S. Typhimurium Delta msbB-induced inflammation was significantly exacerbated in Nod2-/- mice compared to C57Bl/6 mice. In addition, S. Typhimurium DeltamsbB maintained robust intestinal colonization in Nod2-/- mice from day 2 to day 7 p.i., whereas colonization levels significantly decreased in C57Bl/6 mice during this time. Similarly, infection of Nod1-/- and Nod1/Nod2 double-knockout mice revealed that both Nod1 and Nod2 play a protective role in S. Typhimurium DeltamsbB-induced colitis. To elucidate why S. Typhimurium DeltamsbB, but not wild-type S. Typhimurium, induced an exacerbated inflammatory response in Nod2-/- mice, we used HEK293 cells which were transiently transfected with pathogen recognition receptors. Stimulation of TLR2-transfected cells with S. Typhimurium DeltamsbB resulted in increased IL-8 production compared to wild-type S. Typhimurium. Our results indicate that S. Typhimurium DeltamsbB triggers exacerbated colitis in the absence of Nod1 and/or Nod2, which is likely due to increased TLR2 stimulation. How bacteria with "genetically detoxified" LPS stimulate various innate responses has important implications for the development of safe and effective bacterial vaccines and adjuvants.

Document Type: Article
Additional Information: Times Cited: 0 0
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Projects: Future Ocean
Date Deposited: 30 Mar 2015 12:04
Last Modified: 03 Nov 2016 12:34
URI: http://eprints.uni-kiel.de/id/eprint/27240

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