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ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, requires its OspC outer surface protein in order to infect humans and other vertebrates. The bacteria initiate production of OspC when a vector tick begins to feed on host blood, then repress synthesis 1-2 weeks after establishment of mammalian infection. B. burgdorferi that either fail to produce OspC during early stages of infection, or fail to repress production during later stages, are rapidly cleared by the host’s immune system. Since dysregulation of OspC production will inhibit infection, understanding the mechanisms by which B. burgdorferi turns OspC on and off can lead to specific, novel antibacterial therapies. During our studies on the B. burgdorferi SpoVG protein, we discovered that it binds with high affinity to the 5’ end of ospC mRNA. This led us to look further into ospC transcription and translation. We discovered that a 47 nucleotide stretch at the 5’ end of ospC mRNAs is 100% identical in every examined Lyme disease spirochete from throughout the world. This 47 nucleotide sequence forms an almost perfect inverted repeat, which forms an extended stem-loop structure that we hypothesize to inhibit transcription and/or translation of ospC, by pausing or terminating the progress of RNA polymerase. Additionally, we identified a small, noncoding RNA (sRNA) that can basepair with the 5’ repeat, thereby preventing formation of the stem-loop in ospC mRNA, facilitating transcriptional readthrough, and allowing production of OspC protein. Supplemental funds will be used to further characterize how interactions between ospC mRNA and the sRNA influence OspC synthesis, and examine regulation of the sRNA itself. We hypothesize that functional characterization of the sRNA will yield novel targets for improved therapies to cure Lyme disease infections. The requested supplement is associated with the parent R01 grant, in that it initiated from studies of SpoVG, but has led us in an intriguing direction that is not within the scope of the funded grant.
|Effective start/end date||4/1/20 → 3/31/23|
- National Institute of Allergy and Infectious Diseases
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- 1 Active
Stevenson, B. & Garcia, E.
4/1/20 → 3/31/24
Project: Research project