PROJECT SUMMARY/ABSTRACT
Lyme disease, which is caused by infection with the tick-borne pathogen Borrelia burgdorferi, can lead to
inflammatory pathologies affecting the joints, heart, and nervous systems. As there are no vaccines or effective
vector controls against the infection, Lyme disease is and will continue to be a significant public health
concern. This proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, with
specific applications towards understanding the fundamental biology of, and the host interactions with
tickborne pathogens. The overall goal of these studies is to identify candidate B. burgdorferi targets for
prophylactic and therapeutic treatments for Lyme disease.
Isolates of B. burgdorferi display a high level of genetic heterogeneity, and certain genotypes correlate with
increased pathogenesis in humans. High pathogenicity genotypes have been reported to induce a more robust
Type I interferon response from host cells, and blocking Type I interferon abrogates pathology in laboratory
mouse models of Lyme disease; underscoring the importance of Type I interferon in the pathogenesis of Lyme
disease.
Despite the importance of interferon signaling in the pathogenesis of Lyme disease, the bacterial factors
involved in stimulating production of interferon are not well understood. Recently, the presence of the B.
burgdorferi linear plasmid lp36 was shown to correlate with Type I and Type III interferon production from host
cells ex vivo, however the specific genes involved and the consequences during mammalian infection have not
been determined.
We hypothesize that lp36 encodes unidentified virulence determinants required for stimulating production of
interferon from host cells, as well as induction of disease pathology during mammalian infection. By selectively
deleting different regions of lp36 in B. burgdorferi, we will address the following aims in our studies: (1) Define
the lp36 genes required for innate immune cell responses; and (2) Determine the requirement of lp36 genes for
bacterial colonization and induction of pathology during mammalian infection.
Our innovative approach of linear plasmid truncation allows for screening large plasmid regions for the
presence of novel virulence factors. Using systematic truncations of different sizes, we expect to identify the
lp36 genes involved in stimulation of interferon production from host cells, and determine their roles in
pathogen fitness and tissue pathology during infection. This work will move the field of Lyme disease research
forward, as such factors are ideal candidate targets for novel prophylactic and therapeutic treatments for B.
burgdorferi infection and associated immunopathologies.
