Epithelial transcription factor Elf3 mediates host immune responses to microbiota and protects against aerocystitis in zebrafish

Animals defend against infections and other diseases by adaptively responding to the microbiota they encounter. These adaptations are driven by changes in gene expression programs; however, our understanding of the transcription factors regulating host responses to microbiota remains limited. By leveraging gene expression and chromatin accessibility data from zebrafish and mice, we identified the epithelial-specific E74-like ETS transcription factor 3 (<i>Elf3</i>) as a conserved microbially responsive transcription factor. Transcriptomic analysis of gnotobiotic <i>elf3</i> mutant zebrafish larvae revealed that <i>elf3</i> is required for a normal host response to microbiota, including induction of immune response genes. Mutation of <i>elf3</i> led to immune-related pathologies such as inflammation and infection of the swim bladder, granuloma formation, and reduced survival in adulthood. These results establish <i>elf3</i> as an important mediator of host-microbe interactions in zebrafish.IMPORTANCEAnimals use epithelial barriers to protect themselves from the commensal and pathogenic microorganisms they encounter. These epithelia adapt their function in response to microbial-derived signals, and impairments in these adaptive responses can lead to infection and inflammatory disorders. Improved understanding of the mechanisms underlying host adaptation to microbes can thus be expected to lead to new approaches for promoting health in humans and other animals. Here, we identify the epithelial transcription factor E74-like ETS transcription factor 3 (Elf3) as a mediator of host-microbe interactions in zebrafish. Functional genomic approaches indicated that <i>Elf3</i> is upregulated by microbiota in both mouse and zebrafish. Using <i>elf3</i> mutant zebrafish, we find that <i>elf3</i> mediates induction of host immune responses in larval stages and protects against immune-related pathologies and health deterioration in adults. These results advance our understanding of the transcriptional mechanisms mediating host responses to microbes and provide a new Elf3 deficiency model of epithelial and immune pathology.