A new model system for the study of the animal innate immune response to fungal infections

The association of the model organism Caenorhabditis elegans and the fungus Pleurotus ostreatus gives the possibility to study the molecular and genetic mechanisms of the early stages of the spatial and temporal interactions of animals with fungal pathogens. We identified the stages of the infection process of P. ostreatus on the nematode C. elegans. We found that prior to penetration inside a worm a fungal toxin paralyzed and immobilized, but did not kill C. elegans. This finding opens the possibility for the further study of the effect of paralyzing toxins on host organisms. The membrane permeability of paralyzed worms increased dramatically and leakage products initiated the growth of directional hyphae towards the nematodes. The hyphae penetrated into live C. elegans animals either through natural openings or directly by piercing the cuticle. Upon contact with the nematode cuticle, P. ostreatus attached to it, formed appressoria-like structures and infection pegs, piercing the cuticle and penetrating inside the nematode body. The small zones around the penetration loci are of special interest for the evaluation of initial contacts between two organisms and for the study of the C. elegans local defense response against fungal infection.     

Modeling antibiotic resistance in the microbiota using multi-level Petri Nets

Background

The unregulated use of antibiotics not only in clinical practice but also in farm animals breeding is causing a unprecedented growth of antibiotic resistant bacterial strains. This problem can be analyzed at different levels, from the antibiotic resistance spreading dynamics at the host population level down to the molecular mechanisms at the bacteria level. In fact, antibiotic administration policies and practices affect the societal system where individuals developing resistance interact with each other and with the environment. Each individual can be seen as a meta-organism together with its associated microbiota, which proves to have a prominent role in the resistance spreading dynamics. Eventually, in each microbiota, bacterial population dynamics and vertical or horizontal gene transfer events activate cellular and molecular mechanisms for resistance spreading that can also be possible targets for its prevention.

Results

In this work we show how to use the Nets-Within-Nets formalism to model the dynamics between different antibiotic administration protocols and antibiotic resistance, both at the individuals population and at the single microbiota level. Three application examples are presented to show the flexibility of this approach in integrating heterogeneous information in the same model, a fundamental property when creating computational models complex biological systems. Simulations allow to explicitly take into account timing and stochastic events.

Conclusions

This work demonstrates how the NWN formalism can be used to efficiently model antibiotic resistance population dynamics at different levels of detail. The proposed modeling approach not only provides a valuable tool for investigating causal, quantitative relations between different events and mechanisms, but can be also used as a valid support for decision making processes and protocol development.

     

A model for simulating cognate recognition and response in the immune system.

We have constructed a model of the immune system that focuses on the clonotypic cell types and their interactions with other cells, and with antigens and antibodies. We carry out simulations of the humoral immune system based on a generalized cellular automaton implementation of the model. We propose using computer simulation as a tool for doing experiments in machine, in the computer, as an adjunct to the usual in vivo and in vitro techniques. These experiments would not be intended to replace the usual biological experiments since, in the foreseeable future, a complete enough computer model capable of reliably simulating the whole immune would not be possible. However a model simulating areas of interest could be used for extensively testing ideas to help in the design of the critical biological experiments. Our present model concentrates on the cellular interactions and is quite adept at testing the importance and effects of cellular interactions with other cells, antigens and antibodies. The implementation is quite general and unrestricted allowing most other immune system components to be added with relative ease when desired.     

A forward-genetic approach for analysis of the immune system

The completion of the genome sequences of both humans and mice challenges biologists to determine gene function on a vast, whole-organism scale. Both phenotype-based ('forward') and gene-based ('reverse') strategies are being developed to approach this issue. Forward-genetic approaches, however, provide the unique ability of assigning function to genes in an unbiased, global manner that is independent of previous assumptions about gene function. In this article, we compare various genetic technologies for their potential role in dissecting immune-system development and function, with particular emphasis on the worldwide efforts that use chemical mutagenesis as a forward-genetic strategy.     

A monte carlo approach to population dynamics of cells in a HIV immune response model

Summary Using a direct Monte Carlo simulation, population growth of helper T-cells (N _H) and viral cells (N _v) is studied for an immune response model with an enhanced spatial inter-cellular interaction relevant to HIV as a function of viral mutation. In the absence of cellular mobility (P _mob=0), the helper T-cells grow nonmonotonically before reaching saturation and the viral population grows monotonically before reaching a constant equilibrium. Cellular mobility (P _mob=1) enhances the viral growth and reduces the stimulative T-cell growth. Below a mutation threshold (P _c), the steady-state density of helper T-cell (p _H) is larger than that of the Virus (p _v); the density difference Δp _o(=pV−pH) remains a constant at P _mob=1 while −Δp _o→0 as P _mut→P _c at P _mob=0. Above the mutation threshold, the difference Δp _o in cell density, grows with ΔP=P _mut−P _c monotonically: ΔP _o ∞ (ΔP)^β ≃ with β≈0.574±0.016 in absence of mobility, while Δp _o≈6(ΔP) with P _mob=1.     

A model for exploring afferent signals from the immune system to the nervous system

Mechanisms of information transmission from the immune system to the nervous system have been studied. The results of the studies support the assumption that these signals can be transmitted by oligopeptides (the products of limited proteolysis) which are the fragments found in the active sites of many regulatory peptides of the nervous and immune systems. The testing of a synthesized tripeptide (Ser-Lys-Asp) has shown that it inhibits the antibody-forming cells in intact mice only in response to the administration of large antigen doses and exerts a protective effect against viral infection. When added to the culture of the incubated leukocytes from the peripheral blood of the oncological patients, the tripeptide lowers an increased or normal functional activity of natural killers. In rabbits, tripeptide administration brings about a complex long-lasting reorganization of bioelectrical activity in subcortical structures of the brain.     

Time-dependent structural transformation analysis to high-level Petri net model with active state transition diagram

Background  

With an accumulation of in silico data obtained by simulating large-scale biological networks, a new interest of research is emerging for elucidating how living organism functions over time in cells.     

A shape space approach to the dynamics of the immune system

A simple mathematical model of Jerne's immune network is proposed where interactions among idiotypes are set according to their location in a shape space. Although the number of interacting idiotypes is potentially infinite, the simplicity of the model makes it possible to compute the attractors of the dynamics, to define the regions in the four parameters space related to the dynamical behavior and to predict the scaling law giving the number of different antigens that can be presented to the network without triggering dangerous instabilities. It is shown that only a low connectivity regime is safe for the immune network.     

An enhanced agent based model of the immune system response

We describe some recent enhancements introduced in C-ImmSim, a simulator of the immune system response that we have been developing for a number of years along with preliminary results produced by the simulation of the Highly Active Anti-Retroviral Therapy in HIV-1 infected patients.     

A mathematical model for the investigation of the Th1 immune response to Chlamydia trachomatis

Chlamydia are bacterial pathogens of humans and animals causing the important human diseases trachoma, sexually transmitted chlamydial disease and pneumonia. Of the human chlamydial diseases, sexually transmitted disease caused by Chlamydia trachomatis is a major public health concern. Chlamydia trachomatis replicates intracellularly and is characterised by a complex developmental cycle. Chlamydia is susceptible to humoral and cell-mediated immunity. Here we investigate the Th1 cell-mediated immune response against Chlamydia-infected cells as the response changes over the chlamydial developmental cycle. We suggest a form for the immune response over one developmental cycle by modelling the change in the number of intracellular chlamydial particles and assume peptides are presented in proportion to the number of replicating forms of chlamydial particles. We predict, perhaps non-intuitively, that persistent Chlamydia should be induced and forced not to return to the lytic cycle. We also suggest that extending the length of the time of the lytic cycle will effectively decrease the required efficacy of the Th1 response to eliminate the pathogen. We produce plots of active disease progression, control and clearance for varying levels of Th1 effectiveness.     

Nude mice--a model system for studying the cellular basis of the humoral immune response

Mice homozygous for the nu gene fail to develop a thymus. In comparison to spleen cells from +/nu mice spleen cells from nu/nu mice have a deficient 19S PFC response to SRBC when tested in culture or in vivo. This deficiency is due to a lack of “helper” T cells in nu/nu spleen; A cells and B cells appear to be normal. The capacity of nu/nu spleen cells to produce a PFC response in culture can be corrected by the addition of T cells obtained from either the thymuses or the spleens of +/nu mice. In contrast to “helper” T cells obtained from the spleen, “helper” T cells obtained from the thymus appear to require the capacity for proliferation during the response to SRBC.     

A unified discrete model of immune response

In this paper we propose a unified model of immune response in terms of discrete automata describing the concentrations of the cells constituting the immune network. The model of normal immune response proposed by Kaufman, Urbain and Thomas and that of auto-immune response proposed by Weisbuch, Atlan and Cohen are special cases of this unified model. Moreover, this model also describes the immune response in patients infected by the human immunodeficiency virus (HIV), the virus that is known to cause Acquired Immune Deficiency Syndrome (AIDS).     

A dynamical model of human immune response to influenza A virus infection

We present a simplified dynamical model of immune response to uncomplicated influenza A virus (IAV) infection, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells (cytotoxic T-cells and natural killer cells). Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov and Romanyukha [1994. Mathematical model of antiviral immune response. III. Influenza A virus infection. J. Theor. Biol. 167, 323-360], the model is constructed as a system of 10 ordinary differential equations with 27 parameters characterizing the rates of various processes contributing to the course of disease. The parameters are derived from published experimental data or estimated so as to reproduce available data about the time course of IAV infection in a na?ve host. We explore the effect of initial viral load on the severity and duration of the disease, construct a phase diagram that sheds insight into the dynamics of the disease, and perform sensitivity analysis on the model parameters to explore which ones influence the most the onset, duration and severity of infection. To account for the variability and speed of adaptation of the adaptive response to a particular virus strain, we introduce a variable that quantifies the antigenic compatibility between the virus and the antibodies currently produced by the organism. We find that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load.     

The immune system response to Campylobacter infection

Campylobacter may be one of the most common causes of bacterial gastroenteritis (GE) in children. It has recently been suggested that it is one of the bacterial pathogens most likely to infect immune-compromised children, and it may facilitate colonization of enteric pathogens. The immune system response was studied in 12 children with Campylobacter fetus subspecies jejuni (CBJ) infections. Serum concentrations of IgA, IgM, and IgG were analyzed using a Beckman auto-analyzer. Sera specific Ab to CBJ were tested with CBJ specific enzyme-linked immunosorbent assay (ELISA). Mitogen stimulation of lymphocytes was performed to three lectins: Con A, PWM, and PHA. The lymphocyte blast transformation to Campylobacter was studied using the Campylobacter antigen. T-cell subsets were studied using the monoclonal antibodies Leu 2, 3, and 4 (Becton Dickinson). Chemotaxis was measured in modified Boyden chambers; chemotactic stimulants were the Formyl Met Leu Phe, Campylobacter antigen virion, and E. coli 0111 B. Immunoglobulins were normal in nine cases and abnormal in two children previously diagnosed as agammaglobulinemic and one diagnosed as hypoagammaglobulinemic. Specific serum Ab level was significantly higher in the CBJ group, except in the agammaglobulinemic group. Stimulation indices to mitogens and monoclonal subset were in the normal range. The blastogenic transformation to CBJ Ag was decreased compared to normal lectins, and positive and high compared to controls. The chemotactic activity to campylobacter Ag was decreased in comparison to other stimulants. Most CBJ infections are self-limiting due to a normal immune response and collaboration of all cellular limbs. When, however, the immune response is disturbed, we may find a prolonged and complicated course of CBJ.     

Identification of SPAM messages using an approach inspired on the immune system

In this paper, an immune-inspired model, named innate and adaptive artificial immune system (IA-AIS) is proposed and applied to the problem of identification of unsolicited bulk e-mail messages (SPAM). It integrates entities analogous to macrophages, B and T lymphocytes, modeling both the innate and the adaptive immune systems. An implementation of the algorithm was capable of identifying more than 99% of legitimate or SPAM messages in particular parameter configurations. It was compared to an optimized version of the naïve Bayes classifier, which has been attained extremely high correct classification rates. It has been concluded that IA-AIS has a greater ability to identify SPAM messages, although the identification of legitimate messages is not as high as that of the implemented naïve Bayes classifier.     

A new system for estimating the bacterial cheomotactic response applied to a model oligotrophic marine system

A new system to study bacterial responses is described. The method utilizes a device which consists of a beaker into which funnels with attached membranes are inserted. One funnel exudes a test solution and the other funnel a control solution. Samples were retrieved aseptically at a position one cm below the control and the attractant funnels. A positive chemotactic response by a starved marine Gram-negative bacterium towards mixture of low molecular weight substances was observed. This response was detected during the initial phase of starvation. The model allows the experiments to be carried out under conditions which reflect the situation in natural oligotrophic waters. The possibility to measure subcellular quantities in response to a nutrient concentration was demonstrated by the determinationa of the bacterial fatty acid profile.     

A methodological approach to the use of terrestrial invertebrates for the assessment of alluvial wetlands

We review progress toward developing a data-analysis system using invertebrate species lists in wetland evaluation procedures. Species lists for Mollusca, Carabidae (Coleoptera), Empidoidea and Syrphidae (Diptera), derived from samples collected at six stations along a transect established at a site on the floodplain of the River Loire (France) provide the raw data. An initial analysis using a traditional ordination method (Correspondence Analysis) is carried out. A data base was established for the 118 mollusc, carabid and syrphid species recorded, and each species was then treated not as a simple integer, but as an amalgam of digitised attributes deemed responsive to wetland conditions, in a correspondence analysis on instrumental variables. Despite the generalized nature of the attributes as defined for this example, the approach demonstrates a marked increase in interpretability of the output of analysis, in respect of the relation between the species and the floodplain environment. It also highlights the value of use of data pertaining to more than one taxonomic group and of selecting these taxonomic groups on the basis of complementarity of their bioindicator potential.Corresponding Editor: J.T.A. Verhoeven     

A dynamic continuum model for molecular regulation of the humoral immune response.

Based on current concepts of the nature of specific immunocompetent cell surface receptors, hematopoietic stem cell differentiation and membrane dynamics, a simple model is proposed by which the event of immunogen binding by cell surface receptors specifically stimulates a constitutive process. The concept that enhancement of process flows in two directions with time allows for correlation of recent experimental findings into a molecular theory for antibody induction. The Model helps explain antibody specificity, heterogeneity and affinity changes and rationalizes immune memory.