Lyme disease and venereal syphilis, illnesses caused by the spirochetal pathogens Borrelia burgdorferi and Treponema pallidum, respectively, are the principal focus of research in the Radolf laboratory.  Much of our research on these diseases centers about the discovery that B. burgdorferi and T. pallidum have highly unusual outer membranes and that outer membrane ultrastructure is an important determinant of their abilities to cause persistent infection.  In addition to defining outer membrane components, these efforts are directed towards unraveling the complex genetic processes that control expression of outer membrane constituents in diverse environments.  In the case of B. burgdorferi, this work has evolved into an intensive examination of the signaling pathways and transcriptional processes that enable the Lyme disease spirochete to recognize and adapt to environmental stress within the mammalian and arthropod hosts.  Investigation of this process of antigenic change, called differential gene expression, has been facilitated by the availability of whole genomic sequences along with the development of efficient techniques for knocking out selected borrelial genes and introducing new genes, including fluorescent reporter constructs, into the bacterium on plasmid shuttle vectors.

Inflammatory processes mediate clinical manifestations in both Lyme disease and syphilis.  A number of years ago we discovered that both spirochetes have an abundance of lipid-modified proteins, and we subsequently demonstrated that these pathogen associated molecular patterns (PAMPs) are major proinflammatory agonists in Lyme disease and syphilis.  This work led us to the discovery that activation of innate immune cells by spirochetal lipoproteins proceeds via the pattern recognition receptors (PRRs) CD14 and Toll-like receptor 2 (TLR2) Our current objectives are to delineate how these signaling pathways function at the site of infection to cause inflammation and, as a result, tissue damage.  To accomplish these, we have developed innovative in  vivo and ex vivo methodologies, including an experimental human model that enables us to sample skin inflammatory cells for molecular and cellular analysis.