title: Modeling the Role of Lanthionine Synthetase C-Like 2 (LANCL2) in the Modulation of Immune Responses to Helicobacter pylori Infection.
abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leber
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Nuria
authors.initials: N
authors.lastname: Tubau-Juni
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zoccoli-Rodriguez
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Viladomiu
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Vida
authors.initials: V
authors.lastname: Abedi
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Pinyi
authors.initials: P
authors.lastname: Lu
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
mesh_terms: D000818:Animals; D003198:Computer Simulation; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D028044:Phosphate-Binding Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000382:microbiology
chemical_list: C572254:LANCL2 protein, mouse; D008565:Membrane Proteins; D028044:Phosphate-Binding Proteins; D011956:Receptors, Cell Surface; D016753:Interleukin-10