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.