title: Predictive computational modeling of the mucosal immune responses during Helicobacter pylori infection.
abstract: T helper (Th) cells play a major role in the immune response and pathology at the gastric mucosa during Helicobacter pylori infection. There is a limited mechanistic understanding regarding the contributions of CD4+ T cell subsets to gastritis development during H. pylori colonization. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and how CD4+ T cell subsets influenced initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamics of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of a Th17 response and a dominant Th1 response, together with a regulatory response characterized by high levels of mucosal Treg) cells. We also investigated the potential role of peroxisome proliferator-activated receptor γ (PPARγ) activation on the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARγ knockout system when compared to the wild-type simulation. Spatio-temporal, object-oriented ABM approaches suggested similar dynamics in induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, sensitivity analysis predicted a crucial contribution of Th1 and Th17 effector responses as mediators of histopathological changes in the gastric mucosa during chronic stages of infection, which were experimentally validated in mice. These integrated immunoinformatics approaches characterized the induction of mucosal effector and regulatory pathways controlled by PPARγ during H. pylori infection affecting disease outcomes.
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America ; Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Adria
authors.initials: A
authors.lastname: Carbo
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
authors.forename: Mireia
authors.initials: M
authors.lastname: Pedragosa
authors.forename: Monica
authors.initials: M
authors.lastname: Viladomiu
authors.forename: Madhav
authors.initials: M
authors.lastname: Marathe
authors.forename: Stephen
authors.initials: S
authors.lastname: Eubank
authors.forename: Katherine
authors.initials: K
authors.lastname: Wendelsdorf
authors.forename: Keith
authors.initials: K
authors.lastname: Bisset
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoops
authors.forename: Xinwei
authors.initials: X
authors.lastname: Deng
authors.forename: Maksudul
authors.initials: M
authors.lastname: Alam
authors.forename: Barbara
authors.initials: B
authors.lastname: Kronsteiner
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Mei
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D003198:Computer Simulation; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions; D018928:Immunity, Mucosal; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018448:Models, Immunological; D047495:PPAR gamma / Q000276:immunology; D013270:Stomach / Q000276:immunology / Q000382:microbiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology; D058504:Th17 Cells / Q000276:immunology / Q000382:microbiology
chemical_list: D047495:PPAR gamma
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