Chemotactic response and adaptation dynamics in Escherichia coli

Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.Comment: accepted for publication in PLoS Computational Biology; manuscript (19 pages, 5 figures) and supplementary information; added additional clarification on alternative adaptation models in supplementary informatio

Mathematical analysis of the Escherichia coli chemotaxis signalling pathway

We undertake a detailed mathematical analysis of a recent nonlinear ordinary differential equation (ODE) model describing the chemotactic signalling cascade within an {\it Escherichia coli} cell. The model includes a detailed description of the cell signalling cascade and an average approximation of the receptor activity. A steady-state stability analysis reveals the system exhibits one positive real steady-state which is shown to be asymptotically stable. Given the occurrence of a negative feedback between phosphorylated CheB (CheB-P) and the receptor state, we ask under what conditions, the system may exhibit oscillatory type behaviour. A detailed analysis of parameter space reveals that whilst variation in kinetic rate parameters within known biological limits is unlikely to lead to such behaviour, changes in the total concentration of the signalling proteins does. We postulate that experimentally observed overshoot behaviour can actually be described by damped oscillatory dynamics and consider the relationship between overshoot amplitude, total cell protein concentration and the magnitude of the external ligand stimulus. Model reductions of the full ODE model allow us to understand the link between phosphorylation events and the negative feedback between CheB-P and receptor methylation, as well as elucidate why some mathematical models exhibit overshoot and others do not. Our manuscript closes by discussing intercell variability of total protein concentration as means of ensuring the overall survival of a population as cells are subjected to different environments

Quantitative systems toxicology: modelling to mechanistically understand and predict drug safety

Reliable prediction and prevention of adverse drug reactions (ADRs) remains a key challenge in the development of new medicines. Advanced mathematical and computational modelling approaches, which incorporate cutting-edge mechanistic understanding of ADRs in concert with systematically collected data addressing knowledge gaps, are integral components of model-informed drug discovery and development (MID3). These approaches provide a precise, quantitative framework for predicting and mitigating safety risks in the earliest phases of drug development. Here, we highlight recent developments in the burgeoning field of quantitative systems toxicology (QST), including insights into the current state-of-the-art, as well as outcomes from the Innovative Medicines Initiative (IMI) 2 TransQST project. QST models that describe the disruption of cardiovascular, gastrointestinal, hepatic and renal physiological functions following drug exposure are presented, along with recommendations for their application in drug discovery and development

Comparison of Microbiomes from Different Niches of Upper and Lower Airways in Children and Adolescents with Cystic Fibrosis

Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible