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Infection and Immunity, February 2007, p. 706-713, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.01597-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Modification of the Structure of Peptidoglycan Is a Strategy To Avoid Detection by Nucleotide-Binding Oligomerization Domain Protein 1

Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia

Received 3 October 2006/ Returned for modification 6 November 2006/ Accepted 22 November 2006

Nucleotide-binding oligomerization domain (NOD) protein 1 (NOD1) and NOD2 are pathogen recognition receptors that sense breakdown products of peptidoglycan (PGN) (muropeptides). It is shown that a number of these muropeptides can induce tumor necrosis factor alpha (TNF-) gene expression without significant TNF- translation. This translation block is lifted when the muropeptides are coincubated with lipopolysaccharide (LPS), thereby accounting for an apparently synergistic effect of the muropeptides with LPS on TNF- protein production. The compounds that induced synergistic effects were also able to activate NF-B in a NOD1- or NOD2-dependent manner, implicating these proteins in synergistic TNF- secretion. It was found that a diaminopimelic acid (DAP)-containing muramyl tetrapeptide could activate NF-B in a NOD1-dependent manner, demonstrating that an exposed DAP is not essential for NOD1 sensing. The activity was lost when the -carboxylic acid of iso-glutamic acid was modified as an amide. However, agonists of NOD2, such as muramyl dipeptide and lysine-containing muramyl tripeptides, were not affected by amidation of the -carboxylic acid of iso-glutamic acid. Many pathogens modify the -carboxylic acid of iso-glutamic acid of PGN, and thus it appears this is a strategy to avoid recognition by the host innate immune system. This type of immune evasion is in particular relevant for NOD1.

Published ahead of print on 4 December 2006.

Editor: A. D. O'Brien