Sheila Lukehart

Biography and Research Interests

The Lukehart Laboratory focuses on the pathogenesis of syphilis and the immune response Treponema pallidum in humans and in animal models. Our current major interest is the newly-identified polymorphic tpr gene family of T. pallidum. This gene family comprises 2% of the T. pallidum genome and is hypothesized to encode surface-exposed antigens that are important in syphilis pathogenesis, are major targets of the protective immune response, and are promising vaccine candidates.

We have recently demonstrated that one member of the family, TprK, undergoes rapid sequence variation during infection in a host, thus likely contributing to persistence of the organism in immunocompetent hosts. Antibody responses during infection are focused on the variable regions of TprK and are highly specific for TprK variants. Recent studies, conducted in collaboration with Drs. Arturo Centurion and Lorenzo Giacani, have demonstrated that the immune response positively selects for variants that arise during the course of infection; these variants persist to cause chronic infection.

Studies to date have indicated that the protective immune response to Treponema pallidum is mediated by Th1-type CD4+ lymphocytes and infiltrating macrophages. Ongoing projects in the laboratory include the cloning and characterization of major T cell antigens of T. pallidum, including the above Tpr antigens, and investigation of cytokine induction by these antigens.

Bacterial clearance in vivo results from ingestion and killing of opsonized treponemes by macrophages. The laboratory is currently working to identify the surface molecules that are targets of opsonization, and to define the kinetics of and requirements for bactericidal activity by macrophages.

Invasion of the central nervous system by T. pallidum occurs in the early weeks of infection. With Dr. Christina Marra, the laboratory is exploring the immunologic response to T. pallidum within the CNS, and the efficacy of recommended therapy for CNS syphilis in immunocompetent and HIV-infected patients.

We are working with Dr. Christina Marra to develop a useful molecular typing method for strains of T. pallidum and to use this method to examine epidemiological associations of certain strain types with clinical outcomes of infection.

Treponemes that are closely related to T. pallidum cause yaws, bejel, and pinta, which are infections that are acquired in childhood in remote regions of the world. If untreated, these infections can cause serious debilitating sequelae yet, unlike syphilis, these infections do not affect the central nervous system or the fetus in utero. Our lab is using comparative genomics to identify virulence factors that differentiate the agent of syphilis from the agents of these non-venereal treponemal infections.

With funding from the Life Sciences Discovery Fund, our laboratory is working through the Washington Vaccine Alliance to pursue the development of a vaccine for syphilis. The vaccines under investigation are cocktails of recombinant T. pallidum proteins that are being tested with several adjuvants. These studies are conducted in collaboration with Dr. Caroline Cameron (University of Victoria) and the Infectious Diseases Research Institute, Seattle.