MetA is a "thermal fuse" that inhibits growth and protects Escherichia coli at elevated temperatures.

Adaptive stress resistance in microbes is mostly attributed to the expression of stress response genes, including heat-shock proteins. Here, we report a response of E. coli to heat stress caused by degradation of an enzyme in the methionine biosynthesis pathway (MetA). While MetA degradation can inhibit growth, which by itself is detrimental for fitness, we show that it directly benefits survival at temperatures exceeding 50°C, increasing survival chances by more than 1,000-fold. Using both experiments and mathematical modeling, we show quantitatively how protein expression, degradation rates, and environmental stressors cause long-term growth inhibition in otherwise habitable conditions. Because growth inhibition can be abolished with simple mutations, namely point mutations of MetA and protease knockouts, we interpret the breakdown of methionine synthesis as a system that has evolved to halt growth at high temperatures, analogous to "thermal fuses" in engineering that shut off electricity to prevent overheating.

Neutrophils promote venular thrombosis by shaping the rheological environment for platelet aggregation.

In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.

Death Rate of E. coli during Starvation Is Set by Maintenance Cost and Biomass Recycling.

To break down organismal fitness into molecular contributions, costs and benefits of cellular components must be analyzed in all phases of the organism's life cycle. Here, we establish the required quantitative approach for the death phase of the model bacterium Escherichia coli. We show that in carbon starvation, an exponential decay of viability emerges as a collective phenomenon, with viable cells recycling nutrients from cell carcasses to maintain viability. The observed collective death rate is determined by the maintenance rate of viable cells and the amount of nutrients recovered from dead cells. Using this relation, we study the cost of a wasteful enzyme during starvation and the benefit of the stress response sigma factor RpoS. While the enzyme increases maintenance and thereby the death rate, RpoS improves biomass recycling, decreasing the death rate. Our approach thus enables quantitative analyses of how cellular components affect the survival of non-growing cells.

A global resource allocation strategy governs growth transition kinetics of Escherichia coli.

A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms and they remain a topic of active investigation. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations, they are insufficiently quantified for predictive bottom-up modelling. Here we develop a top-down approach, expanding the recently established coarse-grained proteome allocation models from steady-state growth into the kinetic regime. Using only qualitative knowledge of the underlying regulatory processes and imposing the condition of flux balance, we derive a quantitative model of bacterial growth transitions that is independent of inaccessible kinetic parameters. The resulting flux-controlled regulation model accurately predicts the time course of gene expression and biomass accumulation in response to carbon upshifts and downshifts (for example, diauxic shifts) without adjustable parameters. As predicted by the model and validated by quantitative proteomics, cells exhibit suboptimal recovery kinetics in response to nutrient shifts owing to a rigid strategy of protein synthesis allocation, which is not directed towards alleviating specific metabolic bottlenecks. Our approach does not rely on kinetic parameters, and therefore points to a theoretical framework for describing a broad range of such kinetic processes without detailed knowledge of the underlying biochemical reactions.