ENteric Immunity SImulator (ENISI)
The ENteric Immunity SImulator (ENISI) is a simulator of the gastrointestinal (GI) tract mucosal immune responses created for generating and testing hypothesis of mechanisms of immune regulation in response to the presence of resident commensal or pathogenic bacteria. ENISI is an implementation of an agent-based model of individual mucosa-associated lymphoid tissue immune cells each endowed with a program for trafficking and differentiation according to their intrinsic properties, i.e. epithelial cells, dendritic cells, macrophages, T cells, and natural regulatory T cells (Treg). The internal programs specify movement among the epithelium, lamina propria, and blood in response to inflammation-inducing pathogens and tolerance-inducing commensal bacteria. The model focuses on the antagonistic relationship between inflammatory and regulatory (anti-inflammatory) factors whose constant presence characterize mucosal tissue sites in general and gut mucosa in particular.
In its current stage, ENISI is capable of testing hypotheses to predict the net immune response to a pathogen given the complex interplay between both regulatory and inflammatory pathways. In addition, ENISI can be used to identify aspects of competing immune pathways that could likely be manipulated, through pharmacological intervention for instance, to inhibit pathogen invasion, infection, and evolution.
Accurately predicting these outcomes in specific individual backgrounds sets the stage for modeling determinants of a successful infection (host susceptibility), the capacity of the host as an infectious carrier, and pathogen phenotype selection. These are all relevant to devising effective therapeutic approaches that intervene in microbial infection cycles and pathogenic functions.
Through user-manipulation of cell type-specific programs, ENISI allows one to observe the effects of phenotypic changes in individual cell-types, observed in vitro, at the tissue level. As such, it is a translational research tool that allows researcher to:
- Test plausibility of in vitro observed behavior as explanations for observations in vivo in situ,
- Propose behaviors not yet tested in vitro that could be plausible explanations for observations at the tissue level.
- Conduct low-cost, preliminary experiments of proposed interventions/ treatments.
- Indicate useful areas of research through identification of missing data necessary to address a specific hypothesis.
- Perform in silico experiments that help define the best experimental design for successful immunological outcomes.
The tool currently captures dynamics of four possible outcomes in response to pathogen exposure in the presence of tolerance-inducing microflora:
- Complete tolerance that leads to ongoing pathogenic microbe persistence.
- Hypo-inflammation in which a pathogen is not completely eliminated and persists chronically in the host.
- Inflammation that eliminates the microbe, but it ceases prior to extensive tissue damage.
- Hyper-inflammation in which the microbe is eliminated, but at expense of host tissue damage.
Users may modify rules for agent behavior to create in silico experimental conditions by specifying any of the following features of the system:
- Infection specifics: dose and timing of pathogen entry
- Experimental host phenotypes: parameters governing interactions between specific phenotypes to represent changes in cytokine and cytokine-receptor expression
- Host immunological set-point: initial immune cell populations present at the time of infection
- Strain-specific functions of bacteria: specifications of interaction conditions and consequences for the three general strain-types represented, commensal bacteria, tolerogenic bacteria, or inflammatory bacteria such that their behavior mimics that observed in experimental strains.
The ENISI model includes 87 parameters that the user may control through a scripting language described in ENISI 0.9 documentation. Here we provide an interface that allows the user to observe the outcome of a simulated infection with the gastric pathogen Helicobacter pylori under hypothetical experimental conditions that have been pre-configured for past in silico studies.
- Naive wild type (WT) mouse: The only bacteria present in the GI tract are strains of the resident microflora that are assumed to be tolerogenic.
- H. pylori-infected WT mouse: The gastric mucosa of mouse is colonized with a pathogenic strain of the bacterium (i.e., 26695) carrying the cag pathogenicity island.
- H. pylori-infected myeloid cell-specific peroxisome proliferator-activated receptor (PPAR)γ-deficient mouse: The gastric mucosa of genetically modified mouse lacking PPARγ in myeloid cells (macrophages, dendritic cells and neutrophils) is colonized with H. pylori strain 26695. PPARγ is a nuclear receptor for endogenous lipids [i.e., prostaglandins or hydroxy-containing PUFA] that are produced during various homeostatic processes and has been shown to participate in a number of anti-inflammatory mechanisms including induction of anergy in inflammatory T-cells, enhanced regulatory T cell responses, suppression of inflammatory responses by macrophages, differentiation of macrophages towards an M2 phenotype, and suppression of T cell effector responses.
- H. pylori-infected T cell-specific PPARγ-deficient mouse: The gastric mucosa of genetically modified mouse lacking PPARγ in T cells is colonized with H. pylori strain 26695. PPARγ has been shown to modulate CD4+ T cell differentiation upon antigen recognition promoting regulatory responses.
- H. pylori-infected RORγt deficient mouse: The gastric mucosa of retinoic acid receptor-related orphan receptor (ROR)γt knockout mouse is colonized with H. pylori strain 26695. RORγtT is a transcription factor responsible for commitment to the T helper (Th)17 phenotype.