Transcriptional profiling of zebrafish identifies host factors controlling susceptibility to Shigella flexneri

Abstract

Shigella flexneri is a human adapted pathovar of Escherichia coli that can invade the intestinal epithelium, causing inflammation and bacillary dysentery. Although an important human pathogen, the host response to S. flexneri is poorly understood. Zebrafish larvae, highly innovative for genomics, transcriptomics and genetic tractability, represent a valuable animal model to study human infections in vivo. Here we use a S. flexneri-zebrafish infection model to generate mRNA expression profiles of host response to S. flexneri infection at the whole animal level. The signature of early S. flexneri infection (detected at 6 hours post-infection) is dominated by immune response-related processes. Consistent with its clearance from the host, the signature of late S. flexneri infection (detected at 24 hours post-infection) is significantly changed, where only a small set of immune-related genes remain differentially expressed, including gpr84 which encodes a putative G-protein coupled receptor. Using mutant zebrafish lines generated by ENU, CRISPR mutagenesis and the F0 CRISPR knockout method, we show that gpr84-deficient larvae are more susceptible to S. flexneri infection. Together, these results highlight the power of zebrafish to model infection by bacterial pathogens and provide a community resource to investigate host response to S. flexneri infection.