Wolbachia induces host cell identity changes and determines symbiotic fate in Drosophila

Many host-associated bacteria influence the differentiation of their eukaryotic host cells. The association between Wolbachia pipientis and Drosophila melanogaster offers a model for understanding how host-microbe gene expression co-evolves. Using Wolbachia -infected Drosophila cell lines, we show that the w Mel 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 that w Mel tailors its gene expression to host context. In macrophage-like host cells, w Mel expresses pathogenic effectors, whereas in neuron-like cells, w Mel upregulates metabolic genes. Micro-C chromatin contact data revealed that many of these infection-induced changes are epigenetically encoded, with w Mel infection conferring reduced chromatin contacts and widespread transcriptional derepression in D. melanogaster . These findings show that the nature of Wolbachia symbiosis—mutualistic or pathogenic—emerges from host cell environments and suggest new paths for engineering host-specific microbial phenotypes.