Antitoxin HigA orchestrates T3SS/T6SS expression in aquatic pathogen Edwardsiella piscicida

Toxin-antitoxin (TA) systems are widely distributed in bacteria and archaea, playing crucial roles in multiple biological processes. As the type II TA system in Edwardsiella piscicida, HigB contributes to biofilm formation, intracellular propagation, and host infection. Here, we demonstrated that the cognate antitoxin HigA functions as a key virulence transcriptional regulator. RNA-seq and GSEA analysis revealed that HigA orchestrates the expression of genes associated with type III and type VI secretion systems. Extracellular protein profiles further confirmed that HigA promotes the secretion of T3SS/T6SS proteins. In addition, HigA enhances the pathogenesis of E. piscicida in zebrafish. Collectively, our results highlight that HigA functions as a transcriptional activator, integrating TA system regulation into the broader virulence network in E. piscicida.