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 wMel 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 wMel 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, with wMel 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. In BriefWolbachia pipientis reprograms Drosophila cell identity by reshaping host gene expression and chromatin in a cell type-specific manner. Infected cells adopt novel states tailored to wMel strain gene expression, enabling either mutualism or pathogenesis. These findings advance Wolbachia engineering for targeted host cell interactions and symbiont-driven phenotypes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/658111v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1a28035org.highwire.dtl.DTLVardef@18f56fcorg.highwire.dtl.DTLVardef@197f088org.highwire.dtl.DTLVardef@30925c_HPS_FORMAT_FIGEXP M_FIG C_FIG