Cyclic di-GMP in E. coli: Roles in pathogenesis, host-pathogen interactions, and therapeutic potentials

Cyclic di-GMP (c-di-GMP) is a universal bacterial second messenger that orchestrates the transition between motile and sessile lifestyles, thereby shaping microbial physiology, virulence, and persistence. In Escherichia coli (E. coli), c-di-GMP functions as a central integrator of environmental cues, dynamically regulating motility, biofilm formation, energy metabolism, and pathogenicity. Here, we provide a comprehensive synthesis of recent advances in c-di-GMP signaling in E. coli, spanning local signaling modules that control curli and cellulose biosynthesis to global regulatory circuits linking central metabolism, stress adaptation, and virulence gene expression. We further highlight the emerging view of c-di-GMP as a pathogen-associated molecular pattern that interfaces with host immune sensors such as STING and DDX41, extending its biological relevance beyond bacterial physiology. Finally, we discuss the translational potential of targeting c-di-GMP signaling for biofilm disruption, enhancement of bacteriophage-mediated clearance, and vaccine adjuvant design. Collectively, this review positions E. coli as a powerful model to decode the multifaceted biology of c-di-GMP and to inspire novel antimicrobial and immunomodulatory strategies.