Syphilis and Lyme disease are chronic, complex infections caused by the spirochetal bacteria Treponema pallidum and Borrelia burgdorferi, respectively. While syphilis and Lyme disease are transmitted differently (i.e., sexually or through the bite of a tick), they share many common features. These include penetration of the organism through skin, dissemination via the bloodstream, and immune evasion leading to chronic disease. Acute and chronic inflammatory responses are associated with both diseases.
Little is known about the virulence factors or mechanisms of immune responses operative in the immunopathogenesis of syphilis and Lyme disease. The paucity of information about syphilis stems primarily from the inability to cultivate T. pallidum in vitro. B. burgdorferi can be cultivated in vitro, but its complex life cycle (i.e., in ticks and in mammals) has hampered understanding its virulence traits. Also, identification of the proinflammatory molecules of both organisms may hold the keys to clarifying virulence factors, to understanding the invasive and chronic natures of T. pallidum and B. burgdorferi, and to understanding potential spirochetal control through vaccine development.
The major goal of our laboratory program is to identify, characterize, and isolate spirochetal membrane proteins of biological significance to the immunopathogenesis processes of syphilis and Lyme disease. We discovered that the major integral membrane proteins of both T. pallidum and B. burgdorferi are lipoproteins (proteolipids). Bacterial lipoproteins exhibit potent biological activities, such as the ability to activate B cells, macrophages, and other immune effector cells. In syphilis, this has important implications not only to immunopathogenesis, but also for cellular events that likely contribute to HIV transmission (syphilis is an important cofactor for HIV transmission).
Contemporary approaches are being used for the identification, isolation, and characterization of membrane proteins and lipoproteins of T. pallidum and B. burgdorferi of potential relevance to immunopathogenesis and vaccine development. Structural and functional studies of selected integral membrane proteins are underway to understand how the peculiar membrane biology of T. pallidum and B. burgdorferi contributes to the host-parasite relationship, tissue dissemination, and immune evasion. Some of our studies focus on characterizing the membrane topologies (spirochetes have a dual membrane system) of various spirochetal membrane proteins, to clarify host-pathogen interactions. Our discovery of a new alternative sigma factor pathway (RpoN-RpoS) that regulates the expression of key lipoprotein virulence factors in B. burgdorferi also is a new initiative. Various molecular methodologies additionally are being applied to improve the diagnosis of syphilis, congenital syphilis, and Lyme disease.
Our laboratory also recently has embarked upon understanding the membrane biology of Francisella tularensis, a dangerous biosafety level-3 pathogen of potential importance to the US Biodefense Program (bioterrorism).
emerging pathogens/agents of bioterrorism/tularemia
RECENT PUBLICATIONS
R.K. Deka, C.A. Brautigam, X.F. Yang, J.S. Blevins, M. Machius, D.R. Tomchick, & M.V. Norgard, "The PrnA (TP0319; TmpC) lipoprotein represents a new family of bacterial purine nucleoside receptor encoded within an ATP-binding cassette (ABC)-like operon in Treponema pallidum" J.Biol.Chem., 281:8072-8081, 2006
A.H. Smith, J.S. Blevins, G.N. Bachlani, X.F. Yang, & M.V. Norgard, "Evidence that RpoS (SigmaS) in Borrelia burgdorferi is controlled directly by RpoN (SigmaN)" J.Bacteriol., 189:2139-2144
R.K. Deka, C.A. Brautigam, F.L. Tomson, S.B. Lumpkins, D.R. Tomchick, M. Machius, & M.V. Norgard, "Crystal structure of the Tp34 (TP0971) lipoprotein of Treponema pallidum: implications of its metal-bound state and affinity for human lactoferrin" J.Biol.Chem., 282:5944-5958, 2007
J.S. Sheffield, G.D. Wendel, D.D. McIntire, & M.V, Norgard, "The effect of genital ulcer disease on HIV-1 co-receptor expression in the female genital tract" J.Infect.Dis., In Press 2007
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