Role of AmiA in the Morphological Transition of Helicobacter pylori and in Immune Escape

The human gastric pathogen Helicobacter pylori is responsible for peptic ulcers and neoplasia. Both in vitro and in the human stomach it can be found in two forms, the bacillary and coccoid forms. The molecular mechanisms of the morphological transition between these two forms and the role of coccoids remain largely unknown. The peptidoglycan (PG) layer is a major determinant of bacterial cell shape, and therefore we studied H. pylori PG structure during the morphological transition. The transition correlated with an accumulation of the N-acetyl-D-glucosaminyl-β(1,4)-N-acetylmuramyl-L-Ala–D-Glu (GM-dipeptide) motif. We investigated the molecular mechanisms responsible for the GM-dipeptide motif accumulation, and studied the role of various putative PG hydrolases in this process. Interestingly, a mutant strain with a mutation in the amiA gene, encoding a putative PG hydrolase, was impaired in accumulating the GM-dipeptide motif and transforming into coccoids. We investigated the role of the morphological transition and the PG modification in the biology of H. pylori. PG modification and transformation of H. pylori was accompanied by an escape from detection by human Nod1 and the absence of NF-κB activation in epithelial cells. Accordingly, coccoids were unable to induce IL-8 secretion by AGS gastric epithelial cells. amiA is, to our knowledge, the first genetic determinant discovered to be required for this morphological transition into the coccoid forms, and therefore contributes to modulation of the host response and participates in the chronicity of H. pylori infection.
Synopsis Helicobacter pylori is a human pathogen responsible for gastric diseases such as ulcers and gastric cancers. Despite the host's vigorous immune response, H. pylori is capable of persisting for decades in its human host. H. pylori is found in biopsies in two distinct forms, a spiral rod form and a coccoid form. Chaput et al. investigated the molecular mechanisms leading to the transition of H. pylori from a spiral rod–shaped organism to a coccoid organism. The morphological transition is accompanied by modifications of the bacterial cell wall peptidoglycan. The authors have identified the AmiA protein as essential for this morphological transition and modification of the cell wall peptidoglycan. Additionally, the authors show that the cell wall modifications and morphological transition allow these coccoid forms to escape detection by the immune system and therefore could participate in the persistence of H. pylori infection during the lifetime of its human host.