Borrelia burgdorferi surface-localized proteins expressed during persistent murine infection and the importance of BBA66 during infection of C3H/HeJ mice

摘要

Select members of the group Borrelia burgdorferi sensu lato are the causative agents of Lyme disease (LD), a multisystem, potentially chronic disorder with debilitating clinical manifestations including Lyme arthritis, carditis, and neuroborreliosis. Current knowledge regarding the expression of virulence factors encoded by B. burgdorferi and the breadth of their distribution amongst Borrelia species within or beyond the sensu lato group is limited. Some genes historically categorized into paralogous gene family (pgf) 54 have been suggested to be important during transmission to and/or infection of mammalian hosts. By studying the factors affecting the expression of this gene family and its encoded proteins, their distribution, and the disease profile of a bba66 deletion isolate, we aimed to determine the importance of pgf 54 genes in Lyme disease and their conservation amongst diverse Borrelia species. The culmination of the studies discussed in this thesis describe the association of select genes historically categorized into pgf 54 with infectious phenotypes, with the borrelial sigma factor cascade, and the localization of their encoded proteins to the outer surface of the bacterial cell. Together, the expression profiles and localization of these genes/proteins demonstrates that they are regulated by the ċN-ċS cascade, similarly to the known virulence factor, OspC, and that they are found on the outer surface of the cell where they would have the potential to interact with or sense host factors. Moreover, putative orthologs of these genes were detected by Southern blotting and PCR in diverse Borrelia species associated with both Lyme disease and relapsing fever, some of which expressed pH-responsive proteins that were cross-reactive with antibodies specific for orthologs expressed by B. burgdorferi isolate B31. Finally, an insertion-deletion of one of these genes, bba66, was examined in vivo and was found to be infectious in C3H/HeJ mice. Though bba66 was not found to be absolutely required for murine infection in the study presented here, we and other groups hypothesize that bba66 may instead be important during dissemination or adherence to murine cardiac tissue. Thus, future studies are aimed to determine the function and putative importance of BBA66 beyond the establishment of murine infection.