Institute for Integrative Systems Biology

The rise of multidrug-resistant bacteria, particularly biofilm-forming pathogens such as Staphylococcus epidermidis, highlights the urgent need for alternative antimicrobial strategies. Phage therapy, which uses phages to selectively infect and lyse bacterial cells, offers a promising solution. In this study, we evolved the lytic phage vB_Sep_Steph1 under both biofilm and planktonic conditions, using varying initial phage inoculum titers. Whole-genome sequencing of evolved populations revealed recurrent condition-dependent mutations in holins and structural genes with putative depolymerase activity-critical for host recognition and biofilm degradation. Phenotypic improvements in traits such as antibacterial efficacy and replicative fitness were observed to be highly dependent on both the presence of biofilm and the initial phage titer during evolution. Furthermore, some evolved phage lineages could delay bacterial resistance better than the ancestral strain. These findings support the utility of directed phage evolution to improve therapeutic efficacy and robustness, particularly against biofilm-associated infections.

Cellular responses to light stress operate on two timescales: short-term responses, driven by dynamic photosynthetic mechanisms such as non-photochemical quenching (NPQ), and long-term responses, characterized by various physiological and metabolic shifts driven by changes in gene expression. Understanding the coordination within and between these layers represents a major challenge in photosynthesis research. We achieved this in the diatom Phaeodactylum tricornutum using an adjustable photoprotection dial across 10 mutant strains expressing different constitutive levels of the Lhcx1 protein, which determine their latent NPQ capacity. Crucially, a near-identical initial state is preserved among strains, which allows a precise mapping of the causal chain of events initiated by NPQ induction under high light. This unlocks exceptional leverage to examine holistic interactions between functional photosynthesis and gene expression within their natural regulatory architecture. We observe that increasing NPQ maintains the PSII primary acceptor QA in a more oxidized state with little effect on linear electron flow. This oxidation limits PSII photodamage and promotes cyclic electron flow around PSI, which in turn is consistent with enhanced ATP production supporting PSII repair. Moreover, transcriptomic analysis across high-light exposure time suggests that the expression of nearly half of the genome is modulated via NPQ-driven effects. Gene expression profile clustering reveals distinct and coherent transcriptomic regulatory networks. The short-term response is characterized by a strong downregulation of light-harvesting-related genes — independently of NPQ — and an upregulation of oxidative stress response genes that scales inversely with NPQ magnitude. In the long term, most of the transcriptome is deeply impacted by high-light stress in a widely NPQ-dependent manner, highlighting the critical role of this process in shaping photophysiology, which in turn influences gene expression. By engineering a native functional feedback loop into an experimental dial, our approach establishes a generalizable framework for studying the complex interplay between physiology and system-wide biological regulation.

Cells continuously adjust their metabolism to adapt to changing nutrient conditions, a process that in yeast requires tight coordination between metabolic and stress-response pathways. The peroxiredoxin Tsa1, the main cytosolic 2-Cys peroxiredoxin in Saccharomyces cerevisiae , is well-known for its antioxidant role, but there is an increased interest in understanding its contribution to metabolic regulation. Here we show that Tsa1 exerts a broad regulatory influence on central carbon metabolism, through modulation of the Ras/cAMP/PKA nutrient-signalling pathway. Using dynamic flux balance analysis, we demonstrate that deletion of TSA1 leads to a marked reduction in gluconeogenic flux during the post-diauxic phase, resulting in diminished trehalose and glycogen accumulation. The tsa1 Δ mutant displays persistent PKA activation under glucose-depleted conditions, evidenced by sustained phosphorylation of the trehalase Nth1 and impaired nuclear localization of the stress-responsive transcription factor Msn2. Consequently, genes under Msn2/4 control, including those involved in trehalose synthesis, are repressed. Despite normal abundance and activity of the trehalose synthase complex, increased Nth1 protein levels and activity indicate enhanced PKA-dependent trehalose degradation in the absence of Tsa1. Moreover, tsa1 Δ cells exhibit altered cell size homeostasis and defective cell cycle re-entry following glucose replenishment, linking Tsa1-mediated metabolic regulation to proliferative control. Our results show the regulatory function of Tsa1 as a negative modulator of PKA signalling, coordinating the balance between stress protection, carbohydrate metabolism and growth. This study establishes Tsa1 as a key integrative node connecting metabolic and cell cycle regulation in yeast.

Growing evidence suggests that the gut microbiota is closely intertwined with life-history evolution in a wide range of species, including well-studied model organisms like Drosophila melanogaster. Although recent studies have explored the relationship between gut microbiota and female life-history, the link between gut microbiota and male life-history remains relatively unexplored. In this study, we investigated how gut microbiota changes with male age as well as the associations between gut microbiota composition and male life-history traits in D. melanogaster. Using 22 isolines from the Drosophila melanogaster Genetic Reference Panel (DGRP), we measured lifespan, early/late-life reproduction, and early/late-life physiological performance. We characterized the gut microbiota composition in young (5 days old) and old (26 days old) flies using 16S rDNA sequencing. We observed substantial variation in both male life-history traits and gut microbiota composition across isolines and age groups. Using machine learning, we show that gut microbiota composition could predict the chronological age of the organisms with high accuracy. The most important species contributing to machine learning prediction belonged to the Acetobacter and Ralstonia genera. Associations between gut microbiota and life-history traits were also notable, particularly involving different species from the Acetobacter genus. Our findings suggest that taxa such as Acetobacter may be relevant to the evolutionary ecology of host–microbe interactions in male fruit flies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00248-025-02640-y.

Abstract Microbiomes and their hosts influence one another in a complex and dynamic ecosystem. While bacteria in the root microbiome are recognized for their role in plant health, it still remains unclear whether their viral (phage) activity indirectly influences plant growth. Using machine learning-based viral detection tools, we identified a putative 63.7 kb double-stranded DNA prophage in the plant growth promoting rhizobacterium Pseudomonas simiae WCS417 and experimentally confirmed its lysogenic potential. We co-cultivated the GFP-labeled wild-type (WT) and prophage absent (Δphage) strains with Arabidopsis thaliana and Brachypodium distachyon to assess the prophage’s impact on both bacterial host and plant physiology. Our results demonstrate that prophage presence impacted plant root architecture, root exudate metabolic profiles, and shoot biomass under thermal stress without affecting bacterial colonization ability. Collectively, these findings reveal a triadic plant-bacterium-phage axis in the rhizosphere, underscoring a critical role of phages in shaping community dynamics and plant-microbiome interactions.

Water stress challenges global crop productivity, particularly for perennial species such as grapevines, where effective water management is crucial for berry quality and yield. Aquaporins, a family of water channel proteins, play a key role in regulating water transport within plant cells, affecting water uptake and redistribution. Although the transcriptional response of aquaporin genes to water stress in grapevines has been documented, their translational regulation remains less explored. This study investigates the transcriptional and translational dynamics of three Plasma Membrane Intrinsic Proteins and three Tonoplast Intrinsic Proteins in leaves and roots of a grafted 'Pinot Noir' on 'Kober 5BB' rootstock during water deficit conditions and recovery. Aquaporin translation analyzed by polysome profiling and co-sedimentation analysis of their transcripts highlighted that water stress had a general negative effect, although significant only for VviTIP1-3. Conversely, recovery measured at 6h after rewatering was characterized by a boost of translation reactivation for all but one aquaporins. Transcriptional profiling of the same aquaporins revealed significant down-regulation at prolonged stress in roots, highlighting the contribution of aquaporins to osmoregulation and drought tolerance. Moreover, transcriptional modulation resembles a long-term adaptative response to limit water loss. In the leaf, only two specific genes, VviPIP2-5 and VviTIP2-1, were modulated during water deficit and even more during recovery and positively correlated with stomatal conductance and leaf water potential. They represent important regulators of water homeostasis and good candidates for breeding programs. This study uncovered an additional level of aquaporin post-transcriptional control finely tuning vines to changing external conditions.

Abstract Traditional philosophical perspectives have often linked agency to human rationality and intentionality, but biological evidence suggests that agency predates human cognition and manifests in simpler life forms. This chapter explores agency as a biological phenomenon, examining its evolutionary origins and its role in shaping adaptive behavior. By investigating major evolutionary transitions this work frames agency as an integral driver of life’s increasing complexity. The study challenges conventional views by arguing that agency is not merely a product of evolution but an active force influencing evolutionary trajectories. Ultimately, this approach underscores the dynamic interplay between biological organization, environmental interactions, and the emergence of complex behaviors, offering a framework for understanding the evolution of agency beyond human cognition.

Abstract Prokaryotic organisms, encompassing bacteria and archaea, exemplify the simplest life forms and exhibit remarkable evolutionary endurance and adaptability. This chapter explores the pivotal innovations in prokaryotic agency, including secretion, motility, and the emergence of life cycles, which enhanced metabolic and genetic complexity. These mechanisms underscore the adaptability of prokaryotes, enabling them to thrive in diverse environments and contributing to their evolutionary success. Despite their impressive capabilities, prokaryotes face inherent constraints in achieving structural complexity. We conclude by contextualizing these adaptations within a broader evolutionary scenario, highlighting the transition from prokaryotic simplicity to eukaryotic complexity.