Meghna Verma1,2, Josep Bassaganya-Riera1, Andrew Leber1, Nuria Tubau-Juni1, Stefan Hoops1, Vida Abedi1, Xi Chen3, Raquel Hontecillas1. 1. Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, 1015 Life Science Circle, Blacksburg, VA 24061, USA. 2. Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Blacksburg, 1 Riverside Circle, Roanoke, VA 24016, USA. 3. Grado Department of Industrial and Systems Engineering, Virginia Tech, 250 Perry St, Blacksburg, VA 24061, USA.
Abstract
BACKGROUND: Helicobacter pylori causes gastric cancer in 1-2% of cases but is also beneficial for protection against allergies and gastroesophageal diseases. An estimated 85% of H. pylori-colonized individuals experience no detrimental effects. To study the mechanisms promoting host tolerance to the bacterium in the gastrointestinal mucosa and systemic regulatory effects, we investigated the dynamics of immunoregulatory mechanisms triggered by H. pylori using a high-performance computing-driven ENteric Immunity SImulator multiscale model. Immune responses were simulated by integrating an agent-based model, ordinary, and partial differential equations. RESULTS: The outputs were analyzed using 2 sequential stages: the first used a partial rank correlation coefficient regression-based and the second a metamodel-based global sensitivity analysis. The influential parameters screened from the first stage were selected to be varied for the second stage. The outputs from both stages were combined as a training dataset to build a spatiotemporal metamodel. The Sobol indices measured time-varying impact of input parameters during initiation, peak, and chronic phases of infection. The study identified epithelial cell proliferation and epithelial cell death as key parameters that control infection outcomes. In silico validation showed that colonization with H. pylori decreased with a decrease in epithelial cell proliferation, which was linked to regulatory macrophages and tolerogenic dendritic cells. CONCLUSIONS: The hybrid model of H. pylori infection identified epithelial cell proliferation as a key factor for successful colonization of the gastric niche and highlighted the role of tolerogenic dendritic cells and regulatory macrophages in modulating the host responses and shaping infection outcomes.
BACKGROUND:Helicobacter pylori causes gastric cancer in 1-2% of cases but is also beneficial for protection against allergies and gastroesophageal diseases. An estimated 85% of H. pylori-colonized individuals experience no detrimental effects. To study the mechanisms promoting host tolerance to the bacterium in the gastrointestinal mucosa and systemic regulatory effects, we investigated the dynamics of immunoregulatory mechanisms triggered by H. pylori using a high-performance computing-driven ENteric Immunity SImulator multiscale model. Immune responses were simulated by integrating an agent-based model, ordinary, and partial differential equations. RESULTS: The outputs were analyzed using 2 sequential stages: the first used a partial rank correlation coefficient regression-based and the second a metamodel-based global sensitivity analysis. The influential parameters screened from the first stage were selected to be varied for the second stage. The outputs from both stages were combined as a training dataset to build a spatiotemporal metamodel. The Sobol indices measured time-varying impact of input parameters during initiation, peak, and chronic phases of infection. The study identified epithelial cell proliferation and epithelial cell death as key parameters that control infection outcomes. In silico validation showed that colonization with H. pylori decreased with a decrease in epithelial cell proliferation, which was linked to regulatory macrophages and tolerogenic dendritic cells. CONCLUSIONS: The hybrid model of H. pyloriinfection identified epithelial cell proliferation as a key factor for successful colonization of the gastric niche and highlighted the role of tolerogenic dendritic cells and regulatory macrophages in modulating the host responses and shaping infection outcomes.
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