Primed to be strong, primed to be fast: modeling benefits of microbial stress responses

Organisms are prone to different stressors and have evolved various defense mechanisms. One such defense mechanism is priming, where a mild preceding stress prepares the organism toward an improved stress response. This improved response can strongly vary, and primed organisms have been found to respond with one of three response strategies: a shorter delay to stress, a faster buildup of their response or a more intense response. However, a universal comparative assessment, which response is superior under a given environmental setting, is missing. We investigate the benefits of the three improved responses for microorganisms with an ordinary differential equation model, simulating the impact of an external stress on a microbial population that is either naïve or primed. We systematically assess the resulting population performance for different costs associated with priming and stress conditions. Our results show that independent of stress type and priming costs, the stronger primed response is most beneficial for longer stress phases, while the faster and earlier responses increase population performance and survival probability under short stresses. Competition increases priming benefits and promotes the early stress response. This dependence on the ecological context highlights the importance of including primed response strategies into microbial stress ecology

Feedback Loops of the Mammalian Circadian Clock Constitute Repressilator

Mammals evolved an endogenous timing system to coordinate their physiology and behaviour to the 24h period of the solar day. While it is well accepted that circadian rhythms are generated by intracellular transcriptional feedback loops, it is still debated which network motifs are necessary and sufficient for generating self-sustained oscillations. Here, we systematically explore a data-based circadian oscillator model with multiple negative and positive feedback loops and identify a series of three subsequent inhibitions known as “repressilator” as a core element of the mammalian circadian oscillator. The central role of the repressilator motif is consistent with time-resolved ChIP- seq experiments of circadian clock transcription factors and loss of rhythmicity in core clock gene knockouts

Ökologische Effekte von Stressantworten auf Pilzgemeinschaften: Erkenntnisse aus verschiedenen Modellierungsansätzen

Fungi live in highly fluctuating environments and have developed many different strategies to cope with various stressors. Induced stress responses allow them to mount defenses upon experiencing a stress, while saving costs when defense mechanisms are not needed. Many microbes can enhance their defenses using a strategy known as “priming”, which describes the preparation for an upcoming stress after experiencing an environmental cue (called “priming stimulus”) leading to a more effective stress defense. Some soil fungi, for example, perform better under heat stress if they have previously experienced a temperature stimulus. However, just like most induced defenses in microbes, priming has so far been mainly investigated in isolation. How the community context changes the benefit of priming, and vice versa, how priming can change community dynamics, remains unclear. In this thesis, I used several simulation modeling approaches to assess the interplay of the community and induced heat stress defenses. I investigated different priming strategies in microbial populations and communities (Chapter II), and then concentrated on the benefit of heat priming in communities of soil fungi (Chapter III). Finally, I analyzed the effect of induced heat stress defenses in general on fungal interactions (Chapter IV). In Chapter II, I used an ordinary differential equation model to assess how the benefit of the individual priming strategies (namely a strategy granting an earlier, faster or stronger response) changed for varying priming costs and stress durations, as well as under competition. The results showed that the benefit of the different priming strategies for a population highly depended on the stress duration. An early build-up of a stress response enhanced performance and survivability for short stresses, whereas prolonged periods of heat were most efficiently countered with a stronger response, i.e. a higher response level. In the community, priming in general and the early primed stress response in particular were more beneficial than in isolation. I developed a cellular automaton in Chapter III to investigate priming under fungal competition for space. The model simulated radial growth and spatial segregation of fungal colonies growing in a petri dish under heat stress with and without preceding priming cue. The model results showed that compared to isolation, the benefit of priming was dependent on the traits of the different community members, such as their growth rate, heat stress susceptibility or primeability, as well as the time point of community buildup. Therefore, priming could indeed be more beneficial to an organism in the community context, but its benefit was highly variable and could shift competition between two fungi towards either competitor. In Chapter IV, I aimed to further understand the effect of induced heat stress defenses on fungal competition and fungal interactions. I used a partial differential equation model to account for the processes underlying fungal competition and heat stress defenses, namely the production of antifungal compounds that inhibit competitors, as well as the production of heat shock proteins that protect against cellular damage. Including these dynamics beyond the phenomenological level revealed that a heat stress-induced lag phase increased the time for species to accumulate antifungal compounds. A heat stress could therefore lead to altered inhibitor distributions and changed interaction types, e.g. a shift from partial overgrowth to inhibition. This stress-induced lag could not only change interaction types, but could also affect competition in favor of slower growing species, which could mount defenses against faster competitors or block territory with inhibitors. In this thesis, I used different modeling approaches to assess the interplay of microbial induced stress defenses and competition. My results revealed that findings from species in isolation cannot be directly transferred to the community context, because the benefit of induced defenses highly depends on the traits of community members. Moreover, I showed that also different aspects of the community, such as community assembly and composition, can change under the effect of induced defenses. With this work, I achieved to establish a link between the effect of stress responses at the species level and at the community level. The results identify induced stress defenses as an important driver of community dynamics, highlighting the importance of microbial stress ecology for a better understanding of community functioning.Pilze leben in einer sich ständig ändernden Umwelt und haben viele Strategien entwickelt, um verschiedenste Stressfaktoren zu bewältigen. Induzierte Stressantworten erlauben es ihnen, eine Abwehr erst dann aufzubauen, wenn sie einem Stress ausgesetzt sind, während sie Kosten sparen, wenn eine Abwehr nicht benötigt wird. Viele Mikroben können ihre Abwehr auch mit einer Strategie verbessern, die als „Priming“ bekannt ist. Diese Strategie beschreibt die Vorbereitung auf einen bevorstehenden Stress nach dem Erleben eines Umweltreizes (genannt „Primingstimulus“), was zu einer effektiveren Stressabwehr führt. So zeigen zum Beispiel manche Bodenpilze eine höhere Fitness unter Hitzestress, wenn sie vorher eine milde Temperaturerhöhung erlebt haben. Bisher wurde Priming jedoch, so wie die meisten induzierten Stressantworten, hauptsächlich in Isolation untersucht. Wie die mikrobielle Artengemeinschaft den Nutzen von Priming verändert und umgekehrt, wie Priming die Dynamiken der Gemeinschaft verändert, ist unklar. In dieser Arbeit habe ich verschiedene Simulationsmodelle genutzt, um das Zusammenspiel zwischen der Artengemeinschaft und induzierten Hitzestressantworten zu untersuchen. Hierfür habe ich verschiedene Primingstrategien in mikrobiellen Populationen und Gemeinschaften untersucht (Kapitel II) und mich dann auf den Nutzen von Hitzepriming in Gemeinschaften von Bodenpilzen (Kapitel III) sowie den Effekt von induzierten Hitzestressantworten im allgemeinen auf Pilzinteraktionen (Kapitel IV) konzentriert. In Kapitel II habe ich ein gewöhnliches Differentialgleichungsmodell benutzt, um den Nutzen von verschiedenen Primingstrategien zu bewerten (dabei verglich ich Strategien, die eine frühere, eine schnellere oder eine stärkere Stressantwort erlauben) und um zu untersuchen, wie sich dieser Nutzen für verschiedene Primingkosten, Stressdauern und unter Konkurrenz verändert. Meine Resultate zeigten, dass sich abhängig von der Stressdauer verschiedene Strategien als am vorteilhaftesten erweisten. Ein früherer Aufbau einer Stressantwort erhöhte die Fitness und Überlebenswahrscheinlichkeit für kurze Stressdauern, während lange Stressdauern am effektivsten mit einer stärkeren Antwort gekontert wurden. In einer mikrobiellen Gemeinschaft erwies sich Priming im allgemeinen und insbesondere die frühere Primingstrategie als effektiver als in Isolation. Um denn Effekt von Priming im Wettkampf um Terrain zwischen Pilzen zu untersuchen, habe ich in Kapitel III einen zellulären Automaten entwickelt, der radiales Wachstum und räumliche Trennung von Pilzkolonien in einer Petrischale unter Hitzestress mit und ohne Primingstimulus simulieren kann. Die Resultate des Modells zeigten, dass der Nutzen von Priming im Vergleich zur Isolation von den Eigenschaften der Gemeinschaftsmiglieder, wie zum Beispiel deren Wachstumsrate, Hitzeresistenz, oder vom Alter der Gemeinschaft abhängte. Das zeigte, dass Priming unter den Bedingungen der Gemeinschaft in der Tat einen größeren Nutzen aufweisen konnte als in Isolation, aber dass dieser Nutzen sehr variabel war und den Wettkampf zwischen zwei Pilzen zugunsten des einen oder des anderen beeinflussen konnte. Das Ziel in Kapitel IV war es, den Effekt einer induzierten Stressantwort auf die Konkurrenz und die spezifischen Interaktionstypen zwischen Pilzen zu verstehen. Hierfür nutze ich ein partielles Differentialgleichungsmodell, um die Prozesse, die der Konkurrenz und Hitzestressantwort von Pilzen zugrundeliegen, zu untersuchen. Hierbei handelt es sich um die Produktion von antimykotischen Inhibitoren, die das Wachstum von Konkurrenten stoppen, sowie von Hitzestressproteinen, die vor zellulären Hitzeschäden schützen. Die Einbeziehung von Dynamiken jenseits der phänomenologischen Ebene offenbarte, dass ein hitzeinduzierter Wachtsumsstopp in Pilzen den Zeitraum erhöhte, in dem sich Hemmstoffe ansammeln konnten. Daher konnte ein Hitzestress zu veränderter Inhibitorverteilung und veränderten Interaktionstypen führen, z.B. einer Veränderung von partiellem Überwachsen zu gegenseitiger Hemmung. Dieser Wachtsumsstopp konnte nicht nur Interationstypen verändern, sondern auch Konkurrenz zwischen Pilzen zugunsten von langsameren Spezies verschieben, die eine Abwehr gegen schneller wachsende Konkurrenten aufbauen oder Terrain, dass sie nicht schnell bewachsen können, blockieren. In dieser Arbeit habe ich mit verschiedenen Herangehensweisen das Zusammenspiel von mikrobieller Konkurrenz und induzierter Stressantwort untersucht. Meine Resultate offenbarten, dass Erkenntnisse über Spezies in Isolation nicht direkt auf den Gemeinschaftskontext übertragen werden können, da der Nutzen von Stressantworten stark von den Eigenschaften aller Gemeinschaftsmitglieder abhängt. Zudem zeigte ich, dass sich auch Aspekte der Artengemeinschaft, wie etwa die Entstehung und die Zusammensetzung, durch den Einfluss induzierter Abwehrmechanismen verändern können. Diese Arbeit stellt somit eine Verbindug zwischen den Effekten einer induzierten Stressantwort auf Arten- und Gemeinschaftsebene her. Induzierte Stressantworten werden hier als wichtiger Treiber von Gemeinschaftsdynamiken identifiziert, was die Wichtigkeit von mikrobieller Stressökologie für ein besseres Verständnis von Gemeinschaftsfunktionen unterstreicht

Heat stress can change the competitive outcome between fungi – insights from a modelling approach

Under a changing climate, soil fungal communities will increasingly be subject to periods of heat stress. These periods can affect the performance of individual fungi and their competition for space and resources. Competition between fungi is strongly controlled by the exudation of inhibitory compounds, resulting in different competitive outcomes that range from overgrowth of the inferior competitor to a deadlock, where the competing fungi inhibit each other. As heat stress can alter the competitive outcome between fungi, the community composition can also change strongly. So far, a general understanding of the mechanisms that drive the competitive outcome between fungi under heat stress is still missing. However, this understanding is essential to assess important community functions, such as decomposition or mediation of plant nutrition, which strongly depend on the fungal community composition. Here, we used a partial differential equation (PDE) model simulating two fungal competitors in a two-dimensional space, to mechanistically explain the observed change of fungal competition under heat stress. The model describes mycelial growth, the production and secretion of antifungal compounds, and the synthesis of heat shock proteins of interacting colonies. We found a heat stress-induced lag phase favouring the accumulation of antifungal compounds and the build-up of inhibitor fields. This led to a qualitative change of the competitive outcome, reducing the occurrence of overgrowth by two-thirds. The changes in competitive outcome favoured slower-growing species, which benefit more strongly from the additional time during a stress-induced lag to build up a defence or block territory that would otherwise be quickly claimed by faster competitors. Our work is an important step towards understanding how environmental changes may lead to qualitative changes in competitive outcomes. Our results show the importance of explicitly including species interactions into studies of climate change effects.The data files are txt. files. We recommend using R to open them.Funding provided by: Deutsche ForschungsgemeinschaftCrossref Funder Registry ID: http://dx.doi.org/10.13039/501100001659Award Number: 973The dataset contains only simulated data, generated with a mathematical PDE model in Python. The model uses a set of equations to calculate the spread of fungal biomass along a two-dimensional (x,y) grid

Stress priming affects fungal competition ‐ evidence from a combined experimental and modelling study

Priming, an inducible stress defence strategy that prepares an organism for an impending stress event, is common in microbes and has been studied mostly in isolated organisms or populations. How the benefits of priming change in the microbial community context and, vice versa, whether priming influences competition between organisms, remain largely unknown. In this study, we grew different isolates of soil fungi that experienced heat stress in isolation and pairwise competition experiments and assessed colony extension rate as a measure of fitness under priming and non-priming conditions. Based on this data, we developed a cellular automaton model simulating the growth of the ascomycete Chaetomium angustispirale competing against other fungi and systematically varied fungal response traits to explain similarities and differences observed in the experimental data. We showed that competition changes the priming benefit compared with isolated growth and that it can even be reversed depending on the competitor's traits such as growth rate, primeability and stress susceptibility. With this study, we transfer insights on priming from studies in isolation to competition between species. This is an important step towards understanding the role of inducible defences in microbial community assembly and composition

Stable isotope (δ¹³C, d15N), and n-alkane patterns of bryophytes along hydrological gradients of low-centred polygon of the Siberian Arctic

Mosses are a major component of the arctic vegetation, particularly of wetlands. We present C/N ratio, d13C and d15N data of 400 moss samples belonging to 10 species that were collected along hydrological gradients within polygonal mires located on the southern Taymyr Peninsula and the Lena River delta in northern Siberia. Additionally, n alkane patterns of six of these taxa were investigated. The aim of the study is to see whether the inter- and intra-specific differences in biochemical and isotopic signatures are indicative of habitat with particular respect to water-level. Overall, we find high variability in all investigated parameters. The C/N ratios range between 15.4 and 70.4 (median: 42.9) and show large variations at intra-specific level. However, species preferring a dry habitat (xero-mesophilic mosses) show higher C/N ratios than those preferring a wet habitat (meso-hygrophilic mosses). We assume that this mainly originates from the association of mosses from wet habitats with microorganisms which supply them with nitrogen. Furthermore, because of the stability provided by water, they do not need to invest in a sturdy stem-structure and accordingly have lower C contents in their biomass. The d13C values range between -37.0 and 22.5 per mil (median = -27.8 per mil). The d15N values range between -6.59 and +1.69 per mil (median = 2.17 per mil). We find differences in d13C and d15N signatures between both habitat types and, for some species of the meso-hygrophilic group, a significant relation between the individual habitat water-level and isotopic signature was inferred as a function of microbial symbiosis. The n alkane distribution also shows differences primarily between xero-mesophilic and meso-hygrophilic mosses, i.e. having a dominance of n-alkanes with long (n-C29, n-C31) and intermediate chain lengths (n-C25), respectively. Overall, our results reveal that biochemical and isotopic signals of certain moss taxa from polygonal wetlands are characteristic of their habitat and can thus be used in (palaeo-) environmental studies

Principles for circadian orchestration of metabolic pathways

Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo

Effect of parameter alterations on the period (fraction of default value on logarithmic x-scale).

<p>(A) Change of <i>Per2</i> delay. (B) Change of <i>Cry1</i> mRNA degradation rate. (C) Change of Cry1 inhibition strength on Per2. (D) Change of Bmal1 activation strength on <i>Rev-erb-α</i>. The default parameter values, corresponding to 1 on the x-axis, are: <i>Per2</i> delay <i>τ</i>₃ = 3.82, <i>Cry1</i> degradation <i>d</i>₄ = 0.2, <i>Rev-erb-α</i> activation by <i>Bmal1</i> <i>actn</i>_1,2 = 3.26 and <i>Per2</i> inhibition by <i>Cry1</i> <i>inh</i>_4,3 = 0.37. Blue symbols refer to increasing parameters, whereas orange symbols refer to the reverse parameter variation (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005266#pcbi.1005266.s002" target="_blank">S2 Appendix</a> for details).</p