The Role of YebC in persistent infection of the Lyme disease pathogen

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PROJECT ABSTRACT Lyme disease has emerged as a major public health threat in the United States. One of the unique features of the Lyme disease pathogen Borrelia (or Borreliella) burgdorferi (B. burgdorferi) infection is its ability to evade immune responses and cause persistent infection in mammalian hosts. Differential expression of surface antigens and VlsE antigen variation are two major strategies evolved by B. burgdorferi to achieve persistence in mammals. During the transition from early to persistent phase of infection when humoral immunity is activated, this spirochetal pathogen downregulates OspC, a major surface antigen that is required for early phase of infection. Concomitantly, B. burgdorferi upregulates VlsE, a surface lipoprotein that undergoes antigen variation in mammalian hosts. How vlsE is differentially regulated and what controls vlsE recombination are not unknown. We recently discovered a hypothetical ORF (BB0025) in the B. burgdorferi genome, encoding a novel regulator YebC that controls vlsE expression. In this application, we will test the hypothesis that YebC orchestrates differential expression of vlsE during the early and persistent phases of infection (Aim 1). We will also examine whether downregulation of ospC requires YebC during mammalian infection. In addition to regulating vlsE expression, we provide preliminary data supporting the hypothesis that YebC is also involved in regulating the process of vlsE recombination. This will be tested in Aim 2. Upon the successful completion of this project, we will have identified a key regulator involving in vlsE regulation and antigen variation. Not only will it fill a major gap in our understanding of how B. burgdorferi upregulates vlsE expression and activate the vlsE recombination in the mammalian host, but also will open up a new avenue for further elucidating how YebC responds to humoral immune response or other host signals to regulates virulence gene expression. Thus, the outcome of this application will significantly advance our understanding immune evasion and persistent infection of B. burgdorferi and other pathogens in general.