Signal perception to bacterial warfare: Two-component systems mediated regulation of type VI secretion system in the...

The intestinal tract is a complex ecological interface in which host cells and resident microbiota jointly maintain barrier integrity, immune homeostasis, and metabolic balance. Within this ecosystem, pathogenic bacteria must overcome colonization resistance imposed by commensal communities and host defenses to establish infection. The type VI secretion system (T6SS) is a contact-dependent secretion apparatus that delivers effector proteins into bacterial competitors or host cells, thereby contributing to interbacterial competition, microbiota remodeling, and host-pathogen interactions. However, T6SS activity is not constitutive; rather, it is tightly regulated in response to environmental and host-derived cues. Two-component systems (TCSs) are central to this regulation because they sense intestinal signals, including pH variation, nutrient/metal ion availability and host-associated signals, and can convert these inputs into coordinated control of T6SS expression and activity, including, in some systems, assembly, effector deployment, and attack timing. In this review, we discuss how pathogens deploy TCS‑regulated T6SSs to orchestrate offensive antagonism and defensive countermeasures during intestinal infection. Beyond promoting T6SS-dependent antagonism, some TCSs also participate in damage sensing, envelope repair, counterattack responses, and compensatory defense programs. In certain T6SS-deficient contexts, TCS-mediated induction of capsular polysaccharide synthesis may provide an alternative protective strategy against T6SS-mediated killing, highlighting the regulatory plasticity of bacterial defense systems. By integrating current knowledge from signal perception to effector delivery, this review outlines how TCSs fine-tune bacterial competitiveness and resilience in the intestinal microenvironment and identifies key gaps that limit our understanding of TCS-T6SS regulation in vivo.