Genome-Wide Dissection Reveals Diverse Pathogenic Roles Of Bacterial Tc Toxins

Author summaryEntomopathogenic bacteria deploy a range of toxins to combat their insect hosts. The Tc toxins were first identified in Photorhabdus as having potent oral toxicity to insects, with a mode of action distinct from the well-studied Bacillus thuringiensis Cry toxins. As such the Tc toxins have been considered as potential candidates for novel crop protection strategies. This could mitigate against the potential risks of pest insects developing resistance to the traditionally used Cry toxin-based systems. To date, the generality of diverse Tc toxins and their related pathogenic roles has remained mainly obscure. Our analysis has showed Tc toxins are widely distributed among Gram-negative and positive bacterial genomes. A database was constructed including thousands of Tc loci with hundreds of different putative TcC toxic domains, any one of which might represent candidates for the development of future pest control systems. Moreover, the findings of this study are of wider significance because Tc toxin homologues have been shown to be encoded by a range of human pathogens. These include Salmonella and Yersinia, suggesting their potential roles in human infectious diseases. Together, this study describes the characteristics and distribution of Tc toxins among diverse bacterial genera, and provides a new insight into their roles in different pathogenesis mechanisms. This study also describes findings of potential importance to their development as tools for biotechnological applications.Tc toxins were originally identified in entomopathogenic bacteria, which are important as biological pest control agents. Tc toxins are heteromeric exotoxins composed of three subunit types, TcA, TcB, and TcC. The C-terminal portion of the TcC protein encodes the actual toxic domain, which is translocated into host cells by an injectosome nanomachine comprising the other subunits. Currently the pathogenic roles and distribution of Tc toxins among different bacterial genera remain unclear. Here we have performed a comprehensive genome-wide analysis, and established a database that includes 1,608 identified Tc loci containing 2,528 TcC proteins in 1,421 Gram-negative and positive bacterial genomes. Our findings indicate that TcCs conform to the architecture of typical polymorphic toxins, with C-terminal hypervariable regions (HVR) encoding more than 100 different classes of putative toxic domains, most of which have not been previously recognized. Based on further analysis of Tc loci in the genomes of all Salmonella and Yersinia strains in EnteroBase, a "two-level" evolutionary dynamics scenario is proposed for TcC homologues. This scenario implies that the conserved TcC RHS core domain plays a critical role in the taxonomical specific distribution of TcC HVRs. This study provides an extensive resource for the future development of Tc toxins as valuable agrochemical tools. It furthermore implies that Tc proteins, which are encoded by a wide range of pathogens, represent an important versatile toxin superfamily with diverse pathogenic mechanisms.