Structure of Critical Lyme Disease Protein Determined

Scientists have determined the structure of a telltale protein in the Lyme disease bacterium that picks a fight with a patient’s immune system and then successfully hides from the antibodies sent out to destroy it.

In the June 14 edition of the Journal of Biological Chemistry, a team of researchers from the Texas A&M Institute of Biosciences and Technology in the Texas Medical Center (a component of the Texas A&M University System’s Health Science Center in College Station) and The University of Texas Health Science Center at Houston describe the protein’s structure and likely reasons for its ability to simultaneously provoke and dodge an immune response.

Research on the protein has provided a highly accurate avenue for diagnosing the disease, which can be difficult to recognize in many cases, said co-senior author Steven J. Norris, Ph.D., professor and vice chair for research in pathology and laboratory medicine at the UT-Houston Medical School and a professor in the Graduate School of Biomedical Sciences. Findings also explain in part the tenacity of Lyme disease, which can survive in a host for years if left untreated.

The protein, known as VlsE, is found on the surface of the Lyme disease bacterium. Six regions of the protein don’t change as the organism multiplies, while the genetics of six other regions change rapidly and significantly. Using X-ray crystallography, the research team, led by James C. Sacchettini, Ph.D., obtained a detailed structure of the VlsE protein. Sacchettini is professor of chemistry, biochemistry and biophysics and holds the Wolfe-Welch Chair in Science at Texas A&M in College Station, and is the director of the Center for Structural Biology, a jointly held center of Texas A&M’s Houston and College Station campuses.

Understanding the structure of the VlsE protein helps determine the precise location in the protein of the variable and nonvarying portions. This offers important clues as to why the antibodies against the nonvarying regions are ineffective, despite eliciting a strong immune response in more than 90 percent of Lyme disease patients.

The paper illustrated that the nonvarying regions are almost completely buried within the protein and are largely inaccessible to antibodies. The six variable regions, on the other hand, lie mainly on the surface and mask the nonvarying regions from the host’s defense. These changing areas may allow Lyme disease to stay a step ahead of the host’s defenses by confounding the ability of antibodies to bind to VlsE and hence destroying the bacterium.

Lyme disease is a tick-borne illness that can cause a skin rash, flu-like symptoms, and fatigue initially, and ultimately can damage the joints, heart and nervous system. Most cases are easily treated with antibiotics. If not treated early in the infection, Lyme disease can have lingering symptoms in about 10 percent of patients even after treatment. The Centers for Disease Control and Prevention reports 17,730 U.S. cases of Lyme disease diagnosed in 2000, a record high. The disease is concentrated in 12 northeastern states but was found in all but six states in 2000, the most recent year for which statistics are available.

At the Institute of Biosciences and Technology, Christoph Eicken, Ph.D., Vivek Sharma, Ph.D., and Sacchettini are managing a program to elucidate the structures of all outer surface proteins that camouflage the Lyme disease bacterium, Borrelia burgdorferi, and confuse the host’s immune system.

"These structures provide a road map to the development of new diagnostics as well as effective vaccines," Sacchettini said.

While understanding VlsE’s structure has future research applications for illuminating Lyme disease, it has more immediate utility as a diagnostic tool, Norris said. More than 20 percent of Lyme disease victims do not get a distinctive bulls-eye rash at the site of the tick bite or simply fail to notice the rash.

Common lab tests that measure antibody responses to Borrelia burgdorferi can be confounded by previous exposure to the disease and cross-reactivity with other diseases. Using VlsE or a portion of the protein in these tests gets around both of those problems, Norris has found.

Norris’ earlier research established the genetic structure of VlsE, connected the DNA that encodes the protein to the infectivity of Lyme disease, and described the antibody response caused by the protein. UT-Houston co-authors include Matthew B. Lawrenz, a graduate student in the UT-Houston Graduate School of Biomedical Sciences, and John M. Hardham, a former post-doctoral fellow in Norris’ lab.

– With contributions from the Texas A&M Institute of Biosciences and Technology and The University of Texas Health Science Center at Houston

---

©2006 Texas Medical Center

---

E-Mail: tmcinfo@texmedctr.tmc.edu
URL: http://www.tmc.edu/tmcnews/07_01_02/page_04.html