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 ΔmsbB 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 Δ msbB-induced inflammation was significantly exacerbated in Nod2 −/− mice compared to C57Bl/6 mice. In addition, S. Typhimurium ΔmsbB 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 ΔmsbB-induced colitis. To elucidate why S. Typhimurium ΔmsbB, 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 ΔmsbB resulted in increased IL-8 production compared to wild-type S. Typhimurium. Our results indicate that S. Typhimurium ΔmsbB 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.
Highlights
Our results indicate that Nod1 and Nod2 function as modulators of intestinal inflammation by inhibition of TLR2 signaling and thereby prevent excessive triggering of tolllike receptors (TLRs)-dependent inflammation
Typhimurium DmsbB leads to exacerbated cecal inflammation in Nod22/2 mice
TLR4 and Nod2, we compared intestinal inflammation caused by wild-type and DmsbB Salmonella in both C57Bl/6 and Nod22/2 mice
Summary
Typhimurium is a Gram-negative food-borne pathogen causing enterocolitis and it is a major global health burden. Salmonella is recognized by the host through pattern recognition receptors (PRRs) such as tolllike receptors (TLRs) and nucleotide-binding oligomerization domain (Nod)-like receptors (NLRs). Several PRRs detect bacterial cell wall components, e.g. TLR4 recognizes bacterial lipopolysaccharide (LPS), TLR2 recognizes lipoproteins, and Nod and Nod both recognize peptidoglycan degradation products [1]. Nod recognizes muramyl dipeptide (MDP) and the ligand for Nod is mesodiaminopimelic acid (ieDAP) and they are both important factors for host defense against intracellular pathogens [2][3][4]. Activation of PRRs is a crucial step for the host’s immune system to mount an appropriate inflammatory response against bacterial infections
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