Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.10.22.681277

Wolbachia-mediated antiviral protection is driven by its multimodal effects on Drosophila melanogaster metabolism

Walsh, S. M.·Thomson, T. G.·Johnson, K. N.·Brownlie, J. C.·Schirra, H. J.
View original source ↗Export metadata ↓

Abstract

Wolbachia, a common endosymbiont of Drosophila melanogaster, provides a profound antiviral effect in insects. Wolbachia-mediated viral interference has been employed to limit the spread of arboviruses, including dengue. However, the mechanisms underpinning Wolbachia-mediated viral interference are not consistently understood. Previous studies have identified resource competition as a potential mechanism by which Wolbachia disrupts viral replication. Our study uses nuclear magnetic resonance (NMR)-based metabolomics to characterize the bi- and tripartite host-Wolbachia-virus interactions using the model insect Drosophila melanogaster, the protective Wolbachia strain wMel and the pathogenic Drosophila C virus (DCV). The findings reveal that wMel-infected flies showed increased simple carbohydrate catabolism relative to uninfected Drosophila. DCV infection perturbed nucleotide synthesis and nucleotide abundance in Drosophila compared to uninfected Drosophila, driving metabolism to likely meet the viral replication demands imposed on the host. Notably, co-infected Drosophila exhibited a metabolic profile more similar to wMel-infected flies than DCV-infected flies, suggesting that wMel drives metabolism in a direction that at least temporarily inhibits DCV replication. The metabolic profile is indicative of a hypoxic environment that has been known to trigger immune pathways that further contribute to Wolbachia-mediated pathogen blocking. It is probable that Wolbachia-mediated antiviral protection is a multimodal consequence of wMels influence on host metabolism, rather than a single mechanism. These findings will guide future research and contribute to the continued success of Wolbachia-based vector control strategies against RNA arboviruses, potentially leading to novel approaches for defending against such pathogens and improving vector control strategies. Significance StatementWolbachia-mediated antiviral protection has been used extensively to control the spread of insect-borne viruses, with the release of Wolbachia-infected mosquitoes eradicating local dengue transmission in some regions. Despite this real-world impact, how Wolbachia disrupted viruses remained unclear, with three common mechanisms predicted: (1) competition between Wolbachia and virus for host metabolites, or stimulation of host antiviral pathways via (2) immune priming and/or (3) the RNA interference pathway. Our findings reveal that in Drosophila melanogaster, Wolbachia does compete for some metabolites, but it exerts a greater effect by altering host metabolism which in turn creates an intracellular environment unfavorable for viral replication and indirectly triggers an immune response. Thus, the mechanism by which Wolbachia disrupts viruses relies on both metabolic and immune pathways. Understanding these metabolic mechanisms is crucial for optimizing and sustaining this vector control strategy and for shaping future efforts to combat vector-borne diseases.

Explore related subjects

systems biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Walsh, S. M., Thomson, T. G., Johnson, K. N., Brownlie, J. C., Schirra, H. J.. 2025-10-23. Wolbachia-mediated antiviral protection is driven by its multimodal effects on Drosophila melanogaster metabolism. https://doi.org/10.1101/2025.10.22.681277

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Limit-pushing overexpression reveals constraints on protein abundance

Proteins are often classified as toxic or non-toxic without measuring the abundance reached, leaving constraints on tolerable protein abundance unresolved. We established a limit-pushing approach in Saccharomyces cerevisiae combining strong inducible expression with gTOW-mediated high-copy selection to counteract copy-number compensation while measuring protein abundance and growth. Nearly all of approximately 80 chromosome I proteins severely inhibited growth or reduced viability at sufficiently high abundance. We established IE50, the expression level associated with a 50% reduction in growth rate, to quantify their widely varying overexpression tolerance. IE50 was positively associated with predicted structural order and cytoplasmic localization propensity and negatively associated with sulphur content. Single-cell imaging linked higher tolerance to proteins remaining cytoplasmic without becoming aggregation-positive and revealed abundance-dependent changes in localization and organelle morphology. At extreme abundance, Fun12, Nup60, and Pex22 generated distinct large-scale intracellular states through specific sequence regions. These findings establish overexpression toxicity as a quantitative property linked to protein characteristics and reveal both constraints on tolerable abundance and sequence-dependent capacities for intracellular organization.

systems biology↗
bioRxiv2026

Accessing Enzyme Kinetic Data and Prediction Methods at Scale

Enzyme kinetic parameters inform metabolic models, yet experimental measurements are sparse. A growing body of work predicts them from protein and substrate features, but software fragmentation hinders adoption, so downstream tools lock into the most accessible method. We present OpenKinetics Predictor (at predictor.openkinetics.org), an open-source platform integrating thirteen methods in isolated environments behind one interface. The platform optionally reports similarity between query proteins and each method's training data to contextualise reliability. A common featurisation-prediction abstraction keeps it extensible, and independent parties, including original authors, contributed many methods. We pair it with a data portal (at data.openkinetics.org) that exposes CatLog, a curated kinetic dataset, with precomputed embeddings, predicted binding sites, and standardised splits. Both offer a web interface and an API, and the GECKO modelling toolbox already calls the predictor API. As a case study, we predict across an E. coli model and find inter-predictor agreement varies with metabolic context and data availability.

systems biology↗
bioRxiv2026

A thermoregulatory design principle for transitions into hypometabolism

Mammals entering torpor or hibernation undergo an abrupt transition from normothermia to hypothermia, yet how thermoregulation enables this switch remains poorly understood. Here, we identify dynamical signatures that precede these transitions and a mathematical principle that can generate them. In fasting-induced torpor in mice, body-temperature fluctuations increased before torpor onset, providing an early-warning signal that tracked proximity to the transition better than temperature decline alone. A heat-balance model showed that reducing how strongly the effective heat-loss coefficient depends on body temperature reorganizes thermoregulatory stability, allowing a low-temperature equilibrium to emerge while the normothermic state remains stable. This organization is consistent with a symmetry-broken pitchfork involving a saddle-node. Similar increases in temperature fluctuations preceded hibernation onset in hamsters. These findings link pre-transition temperature dynamics to changes in the underlying thermoregulatory landscape and provide a framework for detecting and understanding transitions from normothermia to hypothermia.

systems biology↗