Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Louse-borne relapsing fever (LBRF) is a strictly human disease caused by louse-borne Borrelia recurrentis. To date, LBRF has been a significant burden in several African nations. LBRF may account for up to 27% of hospital admissions. The mortality can be as high as 40%, if left untreated, and low as 1-5% when treated with antimicrobials. LBRF is characterized by fever relapses associated with spirochetemia, which are driven by the antigenic variation system made of vsp and vlp (pseudogenes)genes, allowing spirochetes to evade antibodies. To date, the vsp/vlp system of B. recurrentis remains uncharacterized (knowledge gap), which is in contrast to the well-defined vsp/vlp system of Borrelia hermsii. LBRF research has been hampered by the lack of immunocompetent animal model. Recently, by using the Collaborative Cross (CC) resource, we developed an immunocompetent mouse model. For that, A17 strain was used and the infected mice consistently developed an increasing level of spirochetemia during day 1-3 pi. However, the mice did not develop any detectable spirochetemic relapse(s). Our recent unpublished data demonstrated that, unlike strain A11, B. recurrentis strain A1 developed multiple relapses over a 20-day period in CC046 mice. By whole genome sequencing A1 via PacBio, we were able to define the antigenic variation system of B. recurrentis A1. Based on the presence (or absence) of promoter sequences, a total of 29 vsp/vls pseudogenes, 23 silent vsp/vlp genes, and 6 putative active vsp/vlp genes were identified. The 6 putative active expression genes were separately located on different linear plasmids (lp190, lp55, lp42, lp35, and lp23) and the chromosome, and were adjacent to telomeres. Given that in B. hermsii, there is only a single vsp/vlp expression gene, which is located on a single plasmid and adjacent to the telomere, it is hypothesized that one of the 6 putative active vsp/vlp genes identified in B. recurrentis strain A1 is the vlp/vsp expression site. To test this hypothesis, the following Specific Aim will be pursued: Specific Aim: Deletion one of the six putative active vsp/vlp genes will disable the antigenic variation system of B. recurrentis strain A1. To test the hypothesis, we will produce 6 A1 vsp/vlp knockout mutants by deleting one of the six putative active vsp/vlp genes in each knockout; and the respective six in cis complements. All mutants will then be tested in CC046 mice for their capacity to establish spirochetemic relapses. The novelty of this application is multifold and includes the use of novel mouse model and PacBio data, and proposed application of targeted deletion to generate B. recurrentis mutants. The expected data will provide the insight into the vsp/vlp system of B. recurrentis, the knowledge, which could ultimately be utilized for developing therapeutic measures against LBRF.
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