Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Modifications of the structure of peptidoglycan is a strategy to avoid detection by NOD1

Abstract

Nucleotide-binding oligomerization domain proteins (NOD1 and 2) are pathogen recognition receptors that sense breakdown products of peptidoglycan (muropeptides). It is shown that a number of these muropeptides can induce TNF-alpha gene expression without significant TNF-alpha translation. This translation block is lifted when the muropeptides are co-incubated with lipopolysaccharide, thereby accounting for an apparent synergistic effect of the muropeptides with LPS on TNF-alpha protein production. The compounds that induced synergistic effects were also able to activate NF-kappaB in a NOD1- or 2-dependent manner implicating these proteins in synergistic TNF-alpha secretion. It was found that a diaminopimelic acid-containing muramyl tetrapeptide could activate NF-kappaB in a NOD1-dependant manner, demonstrating that an exposed DAP is not essential for NOD1 sensing. The activity was lost when the alpha-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 alpha-carboxylic acid of iso-glutamic acid. Many pathogens modify the alpha-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.