Abstract
Gluten-related disorders (GRDs) are a group of diseases that involve the activation of the immune system triggered by the ingestion of gluten, with a worldwide prevalence of 5%. Among them, Celiac disease (CeD) is a T-cell-mediated autoimmune disease causing a plethora of symptoms from diarrhea and malabsorption to lymphoma. Even though GRDs have been intensively studied, the environmental triggers promoting the diverse reactions to gluten proteins in susceptible individuals remain elusive. It has been proposed that pathogens could act as disease-causing environmental triggers of CeD by molecular mimicry mechanisms. Additionally, it could also be possible that unrecognized molecular, structural, and physical parallels between gluten and pathogens have a relevant role. Herein, we report sequence, structural and physical similarities of the two most relevant gluten peptides, the 33-mer and p31-43 gliadin peptides, with bacterial pathogens using bioinformatics going beyond the molecular mimicry hypothesis. First, a stringent BLASTp search using the two gliadin peptides identified high sequence similarity regions within pathogen-derived proteins, e.g., extracellular proteins from Streptococcus pneumoniae and Granulicatella sp. Second, molecular dynamics calculations of an updated α-2-gliadin model revealed close spatial localization and solvent-exposure of the 33-mer and p31-43 peptide, which was compared with the pathogen-related proteins by homology models and localization predictors. We found putative functions of the identified pathogen-derived sequence by identifying T-cell epitopes and SH3/WW-binding domains. Finally, shape and size parallels between the pathogens and the superstructures of gliadin peptides gave rise to novel hypotheses about activation of innate immunity and dysbiosis. Based on our structural findings and the similarities with the bacterial pathogens, evidence emerges that these pathologically relevant gluten-derived peptides could behave as non-replicating pathogens opening new research questions in the interface of innate immunity, microbiome, and food research.
Highlights
Celiac disease (CeD) is a chronic, small-intestinal T-cell-mediated autoimmune disease triggered by the ingestion of dietary gluten from common food grains such as wheat, rye, and barley, in genetically predisposed individuals with a prevalence of about 1% in the general population with regional differences [1]
Subcellular localization prediction was performed with Protter version 1.0 [82]. Comparing both sets of pathogen-derived proteins presented in Table 1, the p31-43 similarity regions are located mainly in the C-terminal part of the target proteins; the respective 33-mer similarity regions are randomly distributed across the target proteins (Figures 3–5)
The majority of the similarity regions were identified to be located in disordered or partially disordered regions and solvent-exposed; they are located in areas not prone to aggregation in the bacterial proteins (Figures 3–5)
Summary
Celiac disease (CeD) is a chronic, small-intestinal T-cell-mediated autoimmune disease triggered by the ingestion of dietary gluten from common food grains such as wheat, rye, and barley, in genetically predisposed individuals with a prevalence of about 1% in the general population with regional differences [1]. In 2002, the group of Khosla showed that the immunodominant gluten fragment has sequence similarity with pertactin, a highly immunogenic protein from the bacterium Bordetella pertussis; this result was not further investigated [4]. It recently identified and characterized a number of mimics of HLA-DQ2.5-restricted gliadin determinants derived from the commensal bacterium
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