Wolbachiainduces host cell identity changes and determines symbiotic fate inDrosophila

Many host-associated bacteria influence the differentiation of their eukaryotic host cells. The association betweenWolbachia pipientisandDrosophila melanogasteroffers a model for understanding how host-microbe gene expression co-evolves. UsingWolbachia-infectedDrosophilacell lines, we show that thewMel strain alters host cell states, inducing novel gene expression programs that diverge from known cell types. Transcriptomic co-expression network analysis identified gene expression modules specific to each cell type and infection state, and revealed thatwMel tailors its gene expression to host context. In macrophage-like host cells,wMel expresses pathogenic effectors, whereas in neuron-like cells,wMel upregulates metabolic genes. Micro-C chromatin contact data revealed that many of these infection-induced changes are epigenetically encoded, withwMel infection conferring reduced chromatin contacts and widespread transcriptional derepression inD. melanogaster. These findings show that the nature ofWolbachiasymbiosis—mutualistic or pathogenic—emerges from host cell environments and suggest new paths for engineering host-specific microbial phenotypes.