Princeton: Worm Learns Pathogen Avoidance from Bacteria

Coleen Murphy’s lab at Princeton seeks to find genes that contribute to maintaining the biological processes that exhibit age-related decline using the nematode C. elegans.  They recently explored how the worm develops and passes on learned avoidance of the pathogenic bacterium Pseudomonas fluorescens (PF15) across generations.  C. elegans exhibits transgenerational avoidance of PF15, lasting for four generations. A specific bacterial small RNA (sRNA) from PF15, Pfs1, mediates this avoidance.  Pfs1 is an sRNA of ~200 nt in the region between a Pseudomonas fluorescens sulfate permease family inorganic anion transporter and a type VI secretion system tip protein.

C. elegans appears to acquire bacterial sRNAs by eating the bacteria that produce them. The worm lives in microbe-rich environments and is exposed to various bacterial food sources, some of which are pathogens.  Once inside the worm, components of the RNA inheritance pathway, such as SID-1, are involved in processing and transporting the sRNAs.  SID-1 is a double-stranded RNA transporter required for sRNA-mediated learned avoidance and transmitting sRNA-based information from the germ line to neurons.  After ingestion, the sRNAs enter the worm's system and are acted upon by these internal mechanisms.

Pfs1 targets the C. elegans gene vab-1 via a 16-nucleotide perfect match.  VAB-1 is an ephrin receptor, a component of the Ephrin signaling pathway, having roles in developmental processes such as coordinated cell movements, epidermal morphogenesis, and axon guidance.  Worm vab-1 reduction is necessary for Pfs1-mediated avoidance.  Targeting worm vab-1 with Pfs1 sRNA confers cross-species avoidance of other pathogenic Pseudomonas sp.  This represents an evolved adaptive strategy where C. elegans uses bacterial sRNAs as indicators of pathogen threat to provide a transgenerational survival advantage. 

The research expands our understanding of how host organisms perceive and respond to their microbial environment through trans-kingdom signaling mediated by sRNAs. It highlights the complexity of transgenerational epigenetic inheritance and suggests that seemingly "developmental" genes can play crucial roles in adult behavior and inherited responses to environmental cues. The discovery of multiple bacterial sRNAs targeting different host genes within a common pathway opens avenues for exploring other such interactions and their potential evolutionary significance. This work has implications for understanding host-pathogen dynamics, the mechanisms of epigenetic inheritance, and the potential for using bacterial sRNAs as therapeutic tools.

Seto RJ, Brown R, Kaletsky R, Parsons LR, Moore RS, Balch JM, Gitai Z, Murphy CT. C. elegans transgenerational avoidance of P. fluorescens is mediated by the Pfs1 sRNA and vab-1. Sci Adv. 2025 Apr 25;11(17):eadt3850. doi: 10.1126/sciadv.adt3850. Epub 2025 Apr 23. PMID: 40267186. 

https://www.science.org/doi/10.1126/sciadv.adt3850