Tuesday, January 14, 2025
1/14/2025
DESCRIPTION (Adapted from the Applicant's Abstract): One of the striking observations that has been made about Borrelia burgdorferi in the post-genomic era is its apparent lack of synthetic machinery. B. burgdorferi does not appear to have any genes for the synthesis of amino acids, fatty acids, enzymes cofactors or nucleotides. As a result, the organism is dependent upon its environment to supply these essential nutrients. Many bacteria possess multiple peptide transport systems with different specificities to facilitate the utilization of peptides as a source for amino acids. The B. burgdorferi genome appears to encode for only a single putative peptide transport system. However, unlike many other bacteria which have only a single peptide binding protein for each transport system, it appears that B. burgdorferi encodes for up to 5 peptide binding proteins (OppA-1 to 5) which may share the same integral membrane transport (OppBC) and ATP-binding machinery (OppDF). The B. burgdorferi putative transport system has a high degree of identity to the Opp and Dpp transport systems of E. coli. Using toxic peptide substrates which are known to be taken up by these systems in E.coli, Dr. Hu and coworkers have shown that B.burgdorferi is able to transport peptides from its environment. They have also performed studies in opp of E. coli where the deleted operon is replaced by plasmids expressing B. burgdorferi OppA-1 and E. coli OppBCDF or E.coli OppA and B. burgdorferi OppBCDF. Using toxic peptides to inhibit the growth of the bacteria, they have shown that B. burgdorferi Opp proteins are capable of complementing their E.coli counterparts to transport peptides. The central hypothesis of this project is that B. burgdorferi uses its 5 substrate binding proteins to broaden substrate specificity and compensate for its paucity of peptide transporters. The first goal of the project will be to test this hypothesis by defining the substrate specificities of each B. burgdorferi OppA and subtype. In addition to their nutritional role, the peptide transport systems of other bacteria play important roles in environmental signaling with diverse interactions ranging from quorum sensing to peptide chemotaxis. Very little is currently known about what stimulates B. burgdorferi to multiply and move from the tick gut to the salivary glands and into the mammalian host as the tick takes its blood meal. Dr. Hu's group believes that the Opp system of B. burgdorferi may be part of a coordinated response of the organism to environmental shifts as it moves from its tick to mammalian hosts and back again. They will test this hypothesis by examining changes in expression of the various Opp proteins as the organism moves from host to host. They will also test the hypothesis that one or more of the OppA proteins of B. burgdorferi may be involved in chemotaxis of the organism. This group believes that a better understanding of the peptide transport system of B. burgdorferi will broaden existing knowledge about how the organism adapts to its multiple hosts as well as the role that these adaptations play in the pathogenesis of Lyme disease, and may eventually lead to the development of novel therapeutics in the treatment of Lyme disease.
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