Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Perturbation Centrality and Turbine: A Novel Centrality Measure Obtained Using a Versatile Network Dynamics Tool

Analysis of network dynamics became a focal point to understand and predict changes of complex systems. Here we introduce Turbine, a generic framework enabling fast simulation of any algorithmically definable dynamics on very large networks. Using a perturbation transmission model inspired by communicating vessels, we define a novel centrality measure: perturbation centrality. Hubs and inter-modular nodes proved to be highly efficient in perturbation propagation. High perturbation centrality nodes of the Met-tRNA synthetase protein structure network were identified as amino acids involved in intra-protein communication by earlier studies. Changes in perturbation centralities of yeast interactome nodes upon various stresses well recapitulated the functional changes of stressed yeast cells. The novelty and usefulness of perturbation centrality was validated in several other model, biological and social networks. The Turbine software and the perturbation centrality measure may provide a large variety of novel options to assess signaling, drug action, environmental and social interventions. The Turbine algorithm is available at: http://www.turbine.linkgroup.huComment: 21 pages, 4 figues, 1 table, 58 references + a Supplement of 52 pages, 10 figures, 9 tables and 39 references; Turbine algorithm is available at: http://www.turbine.linkgroup.h

Nonparametric Simulation of Signal Transduction Networks with Semi-Synchronized Update

Simulating signal transduction in cellular signaling networks provides predictions of network dynamics by quantifying the changes in concentration and activity-level of the individual proteins. Since numerical values of kinetic parameters might be difficult to obtain, it is imperative to develop non-parametric approaches that combine the connectivity of a network with the response of individual proteins to signals which travel through the network. The activity levels of signaling proteins computed through existing non-parametric modeling tools do not show significant correlations with the observed values in experimental results. In this work we developed a non-parametric computational framework to describe the profile of the evolving process and the time course of the proportion of active form of molecules in the signal transduction networks. The model is also capable of incorporating perturbations. The model was validated on four signaling networks showing that it can effectively uncover the activity levels and trends of response during signal transduction process

Single-Cell Transcriptional Analysis of Normal, Aberrant, and Malignant Hematopoiesis in Zebrafish

Hematopoiesis culminates in the production of functionally heterogeneous blood cell types. In zebrafish, the lack of cell surface antibodies has compelled researchers to use fluorescent transgenic reporter lines to label specific blood cell fractions. However, these approaches are limited by the availability of transgenic lines and fluorescent protein combinations that can be distinguished. Here, we have transcriptionally profiled single hematopoietic cells from zebrafish to define erythroid, myeloid, B, and T cell lineages. We also used our approach to identify hematopoietic stem and progenitor cells and a novel NK-lysin 4+ cell type, representing a putative cytotoxic T/NK cell. Our platform also quantified hematopoietic defects in rag2E450fs mutant fish and showed that these fish have reduced T cells with a subsequent expansion of NK-lysin 4+ cells and myeloid cells. These data suggest compensatory regulation of the innate immune system in rag2E450fs mutant zebrafish. Finally, analysis of Myc-induced T cell acute lymphoblastic leukemia showed that cells are arrested at the CD4+/CD8+ cortical thymocyte stage and that a subset of leukemia cells inappropriately reexpress stem cell genes, including bmi1 and cmyb. In total, our experiments provide new tools and biological insights into single-cell heterogeneity found in zebrafish blood and leukemia

Evaluation of Chemical and Mineralogical Transformation of Iron in Different Soils in Saturated and Field Capacity Conditions

Introduction: Redox potential is one of the most important factors affecting on the solubility of iron minerals in soil. Decreasing redox potential in soil reduces Fe3+ to Fe2+, thereby affecting on solubility of Fe minerals. Application of organic matter to soil under waterlogging condition, decrease redox potential and as a consequence, accelerate the transformation of Fe minerals. The objectives of this study were: 1- The effect of waterlogging on the soluble total Fe concentration and transformation of Fe minerals in different soil pH values. 2- The indirect effects of organic matter on solubility of Fe minerals by changing the redox potential of the soils. Materials and Methods: A study was conducted to determine the effects of redox potential on solubility of Fe and transformation of Fe minerals during the time. Four agricultural soils were selected from different regions of Iran. The soil samples were treated with 0 (C)and 2% (O) alfalfa powder and then incubated for 12 weeks under 60% Field capacity (F) and waterlogged conditions (S). Subsamples were taken after 1and 12 weeks of incubation and the redox potential, pH value, electrical conductivity (EC), soluble cations (such as Ca2+, Mg2+, K+ and Na+) and anions (such as Cl-, SO42-, PO43- and NO3- ) and soluble Fe concentrations in the subsamples were measured. Concentrations of Fe2+ and Fe3+ species in soil solution were also predicted using Visual MINTEQ speciation program. Mineralogical transformation of Fe minerals was also determined by X-ray diffraction (XRD) technique. Results and Discussion: The results in 60% Field capacity condition showed that pH value by organic matter (alfalfa powder) application (OF) increased significantly (p≤ 0.05) in acid and neutral soils and decreased in calcareous soils when compared to the control (CF). Organic matter is usually capable of lowering pH of alkaline soils by releasing hydrogen ions associated with organic anions or by nitrification in an open system. On the other hand, it may cause pH to increase in the acid soils either by mineralization of organic acids to carbon dioxide (CO2) and water (thereby removing H+) or by the alkaline nature of the organic residues. This treatment increased soluble total Fe concentration in all soils. It is clear that decomposition of organic matter cause to produce soluble organic compounds and form soluble complexes with Fe, thereby increasing soluble total Fe concentration. Waterlogging (CS) decreased redox potential of the soils gradually with the incubation time, especially in the neutral soil and alfalfa powder application (OS) accelerated this decreasing redox potential. The decrease rates by waterlogging in acid, neutral and two calcareous soils were 2, 3.6, 1.5 and 1.7folds, respectively compared to the control. The soluble total Fe concentration in CS compared to CF treatment increased significantly (p≤ 0.05) in all soils except in acid soil. This increasing was continued with time in all soils except in neutral soil. An important point that OS compared to CS treatment enhanced the soluble total Fe in acid and neutral soils, whereas decreased it in both calcareous soils. However, soluble total Fe increased during the incubation time in all soils except in neutral soil. The increase rates in week 12 relative to week 1were 3.4, 2.2 and 1.8 folds in acid and two calcareous soils, respectively. The decrease of soluble total Fe in the neutral soil is probably attributed to more severe decrease of redox potential in the soil when compared to the other soils. The solubility diagrams and X-ray diffraction results confirmed the formation of pyrite in the acid and neutral soils and the formation of siderite in one of the calcareous soils. Conclusion: In aerobic condition, organic matter application increased the concentration of soluble total Fe and changed Fe-controlling mineral from soil-Fe to amorphous Fe. Waterlogging decreased redox potential and Fe-controlling mineral changed to pyrite and/or siderite, depending on CO2 pressure and pH value of the soils. It might be pointed out that severe reduction of the redox potential decreases soluble Fe through the formation of insoluble Fe minerals such as Fe sulfides. It is concluded that waterlogging soils can provide available Fe to the plant, though severe decrease of redox potential, by application of organic mater, may decrease Fe availability