Structure and function of Burkholderia contact-dependent growth inhibition (CDI) systems

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ABSTRACT Social interactions between bacteria impact infectious disease transmission and progression. The molecular mechanisms underlying bacteria-bacteria competition and communication also represent a largely unexplored set of therapeutic targets that could be manipulated to treat or prevent infections. Contact-dependent growth inhibition (CDI) is a phenomenon in which Gram-negative bacteria deliver the toxic C-terminus of a large, polymorphic surface protein (BcpA) to the cytoplasm of neighboring bacteria upon direct cell-cell contact, inhibiting the growth of the targeted recipient cell unless it produces an appropriate immunity protein (BcpI). While CDI systems have been investigated almost exclusively for their ability to mediate inter-bacterial competition, our previous work indicated that CDI systems also facilitate inter-bacterial communication by inducing specific gene expression and phenotypic changes in immune recipient bacteria (those producing the appropriate immunity protein, BcpI). Thus, CDI systems enable bacterial self/nonself discrimination through several overlapping mechanisms, all of which could be exploited therapeutically. However, fundamental gaps in knowledge of CDI system molecular function prevent a clear understanding of how these proteins impact bacterial sociality and limit the development of CDI system-based antimicrobials, decontaminants, or vaccines. Thus, our long term goal is to identify the molecular mechanisms underlying CDI system function toward manipulating these proteins for the treatment or prevention of infectious disease. Our preliminary data show that Burkholderia species provide a tractable model system for interrogating CDI system biology. This proposal seeks to understand how BcpA is delivered from one bacterium to another and how this process shapes bacterial behavior. Toward these goals, the proposal tests the hypothesis that Burkholderia BcpA exchange is controlled by BcpA-specific domains, recipient cell receptors, and the physiological state of the recipient cell, which together impact microbial community development. The proposed model will be tested by (1) identifying the recipient factors that impact BcpA import, and (2) defining BcpA domains responsible for maintaining appropriate delivery to recipients and testing the role of BcpA delivery in Burkholderia communities. Together, this research will provide critical insight into a specific mechanism of bacterial cell-cell communication, leading to advancement in the prevention or treatment of bacterial infections.