Wolbachia, an intracellular bacterial symbiont, exhibits antiviral effects in insects and has been employed to limit the spread of arboviruses. However, the mechanisms underlying this interference are not consistently understood. Our study employs nuclear magnetic resonance (NMR)-based metabolomics to characterise 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 and elevated purine metabolite levels 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 wMel generates a metabolic environment where there is competition for host metabolites between wMel and DCV inhibiting viral replication. The study also suggests that wMel competes with the host for oxygen, creating a hypoxic environment that generates reactive oxygen species (ROS). ROS are effector molecules well known to trigger specific immune pathways that have been previously proven to contribute to Wolbachia-mediated antiviral protection.
We therefore propose that Wolbachia-mediated antiviral protection should be viewed as a multimodal response resulting from wMel's influence on host metabolism, rather than a single mechanism. Results suggest that wMel drives metabolism in a direction that at least temporarily inhibits DCV replication and is metabolically similar to single wMel infections; in doing so, it concomitantly triggers immune pathways that contribute towards Wolbachia-mediated pathogen blocking. This perspective may 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.