Pathogenic Mechanisms of the Spirochetes Borrelia burgdorferi and Leptospira interrogans:

Borrelia burgdorferi, the Causative Agent of Lyme Disease
B. burgdorferi have evolved mechanisms by which they can persistently infect both vertebrate and arthropod hosts, and be transmitted from tick to mammal and back again. To do so, B. burgdorferi recognize environmental cues and respond accordingly by producing only those proteins appropriate for each point in the infectious cycle. We are developing an understanding of the mechanisms by which B. burgdorferi regulate synthesis of proteins involved in mammalian and tick infection, and the functions of those proteins. Major aspects of our research are:

Regulation of B. burgdorferi erp Gene Expression.  Individual Lyme disease spirochetes can encode as many as 13 different members of the Erp protein family. Our studies indicate that regulation of Erp protein expression occurs during the bacteria's natural infectious cycle. Although we have observed that B. burgdorferi regulate erp gene transcription in response to various external stimuli, including temperature and certain chemical signals, very little is known about how these bacteria sense the environment or control gene expression. Research projects include characterization of the novel proteins we identified that bind erp promoter DNA and thorough definition of the regulatory pathways involved in controlling erp expression.

Structure / Function Studies of B. burgdorferi Erp Proteins.  Research in our laboratory has demonstrated that all of these proteins are expressed simultaneously, and they are exposed to the external environment on the bacteria's outer membrane. Some Erp proteins bind complement factor H, an important regulator of the vertebrate host's innate immune system. It is hypothesized that these interactions prevent B. burgdorferi from being killed by host complement. Other Erp proteins can bind components of host extracellular matrix, and are hypothesized to play roles in bacterial adherence to host tissues during human infection.  Research projects include definition of mechanisms by which Erp proteins adhere to their ligands, and characterization of additional ligands of Erp proteins.

Other B. burgdorferi adhesins.  We identified several additional borrelial adhesins that are unrelated to the erp family.  These include novel surface-exposed outer membrane proteins that bind human laminin and fibronectin.  Research projects include characterization of adhesin-ligand interactions and of the mechanisms controlling expression of adhesins during mammalian and tick infection.

Leptospira interrogans, the Causative Agent of Leptospirosis
Leptospirosis is a significant cause of morbidity and mortality in tropical and semitropical areas throughout the world. It is a threat to both indigenous populations and to military personnel, aid workers and tourists.  It is also becoming increasingly recognized as an emerging human health threat in rural, suburban and urban areas throughout the USA.

L. interrogans Len Proteins.  We discovered that infectious leptospires produce several paralogous outer membrane proteins with affinities for host tissue components, including laminin, fibronectin and serum factor H.  Research projects include characterization of Len protein expression during mammalian infection, functional analyses of Len-ligand interactions, and regulatory mechanisms controlling Len expression.

Additional Research Projects in the Stevenson Lab.  We are also working on a number of other projects, some of which are still in the exploratory stage and others of which are subjects of pending grant proposals.  These include characterization of the EbfC/YbaB family of novel DNA binding proteins we discovered (which are produced by almost every known species of bacteria), characterization of novel L. interrogans and B. burgdorferi antigens, and elucidation of regulatory pathways controlling various other spirochetal proteins involved in human infections.

Research in our laboratory is funded by the following grants:

National Institutes of Health grant RO1-AI044254: Analysis of Borrelia burgdorferi Erp proteins, 2000-2011, $250,000 direct costs per year.

National Institutes of Health grant R21-AI078111: Leptospira interrogans Len adhesins, 2008-2010, $175,000 direct costs per year.

National Institutes of Health grant RO1-AI053101: Borrelia burgdorferi LuxS-mediated quorum sensing, 2003-2008, $225,000 direct costs per year.

National Research Fund for Tick-borne Diseases Pilot Project Award: Studies into the mechanism of Borrelia burgdorferi vlsE recombination, 2007-2008, $50,000 total direct costs.

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Links to other sites

(these links are outside the Univeristy of Kentucky)

B. burgdorferi links:

• TIGR B. burgdorferi genome page
• Annotated B. burgdorferi strain B31 plasmid analyses

Lyme disease information links:

• Centers for Disease Control and Prevention (CDC) Lyme Disease
• European Union Concerted Action on Lyme Borreliosis (EUCALB)
• American College of Physicians

Other spirochete sites:

• International Leptospirosis Society page
• American Leptospirosis Research Conference page

Some colleagues' pages:

• Patti Rosa, Ph.D.
• Tom Schwan, Ph.D.
• Wolf Zückert, Ph.D.
• Mark Wooten, Ph.D.
• Sherwood Casjens, Ph.D.
• Jon Takemoto, Ph.D.
• George Chaconas, Ph.D.