Abstract
Many Gram-negative bacterial pathogens express contact-dependent growth inhibition (CDI) systems that promote cell-cell interaction. CDI+ bacteria express surface CdiA effector proteins, which transfer their C-terminal toxin domains into susceptible target cells upon binding to specific receptors. CDI+ cells also produce immunity proteins that neutralize the toxin domains delivered from neighboring siblings. Here, we show that CdiAEC536 from uropathogenic Escherichia coli 536 (EC536) uses OmpC and OmpF as receptors to recognize target bacteria. E. coli mutants lacking either ompF or ompC are resistant to CDIEC536-mediated growth inhibition, and both porins are required for target-cell adhesion to inhibitors that express CdiAEC536. Experiments with single-chain OmpF fusions indicate that the CdiAEC536 receptor is heterotrimeric OmpC-OmpF. Because the OmpC and OmpF porins are under selective pressure from bacteriophages and host immune systems, their surface-exposed loops vary between E. coli isolates. OmpC polymorphism has a significant impact on CDIEC536 mediated competition, with many E. coli isolates expressing alleles that are not recognized by CdiAEC536. Analyses of recombinant OmpC chimeras suggest that extracellular loops L4 and L5 are important recognition epitopes for CdiAEC536. Loops L4 and L5 also account for much of the sequence variability between E. coli OmpC proteins, raising the possibility that CDI contributes to the selective pressure driving OmpC diversification. We find that the most efficient CdiAEC536 receptors are encoded by isolates that carry the same cdi gene cluster as E. coli 536. Thus, it appears that CdiA effectors often bind preferentially to "self" receptors, thereby promoting interactions between sibling cells. As a consequence, these effector proteins cannot recognize nor suppress the growth of many potential competitors. These findings suggest that self-recognition and kin selection are important functions of CDI.
Highlights
Contact-dependent growth inhibition (CDI) systems mediate the transfer of protein toxins between Gram-negative bacteria
The contact-dependent growth inhibition (CDI) system from Escherichia coli EC93 was the first to be characterized and its CdiA toxin recognizes a receptor (BamA) that is identical in virtually all E. coli isolates
Because sibling cells are immune to CdiAmediated growth inhibition, these findings raise the possibility that toxin exchange may be used for communication and cooperative behavior between genetically identical bacteria
Summary
Contact-dependent growth inhibition (CDI) systems mediate the transfer of protein toxins between Gram-negative bacteria. CdiAEC93 binds to BamA on the surface of neighboring E. coli cells, delivers its C-terminal toxin domain (CdiA-CTEC93) into the target cell to inhibit growth [4]. Inter-sibling toxin exchange does not induce growth arrest because the cdi locus encodes the CdiIEC93 immunity protein, which neutralizes CdiA-CTEC93 toxicity [1, 7]. CDI systems are typically encoded on plasmids and genomic islands and are not necessarily found in all isolates of given species.
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