Molecular mechanisms and regulatory networks governing Yersinia biofilm formation and host adaptation.

The genus Yersinia includes three human pathogens-Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica-where biofilm formation plays distinct roles in transmission and environmental persistence. All three species share the core biofilm machinery-the hmsHFRS operon, encoding enzymes for poly-β-1,6-N-acetylglucosamine (PNAG) exopolysaccharide production, and the c-di-GMP signaling controlling this production-but their regulatory networks and biofilm outputs differ. Transcriptional control of hms involves an integrated network that includes the Rcs phosphorelay (reshaped by rcsA pseudogenization), PhoP/PhoQ, EnvZ/OmpR, BarA/UvrY, Fur/Zur, CRP-cAMP, RovM/RovA, and multiple sigma factors. Post-transcriptionally, the Hfq-sRNA and CsrA-CsrB/CsrC systems modulate gene expression; the latter is directly validated in Y. pestis and Y. pseudotuberculosis, whereas its role in Y. enterocolitica is inferred from genomic conservation. At the translational and enzymatic levels, polyamines sustain Hms protein production, while redox signals govern the HmsC-HmsD disulfide switch, controlling diguanylate cyclase activity. This multi-layer architecture ensures that biofilm output is tuned to species-specific ecological niches. In host adaptation, Y. pestis transitioned from a foodborne enteric pathogen to a flea-borne lifestyle through key genetic events-acquisition of ymt, pseudogenization of rcsA, inactivation of y2909/y3389, and ureD-which are not shared with Y. pseudotuberculosis or Y. enterocolitica, thereby explaining their different biofilm-dependent transmission strategies. Studies in Caenorhabditis elegans have identified host O-glycosylation modifications as receptors for biofilm attachment. This review summarizes progress on the molecular mechanisms, regulatory networks, and host-adaptive functions of Yersinia biofilm formation and proposes future research directions to address knowledge gaps. Future priorities include the identification of c-di-GMP effectors, flea-specific signals, 3D biofilm imaging, and CRISPR-based detection.