By Dean Haycock
Special To BioWorld Today
Leprosy and Lassa fever share few features besides pathogenicity and alliteration. Leprosy, or Hansen's disease, is an ancient affliction. Leprotic bones date back to A. D. 500. Lassa fever entered Western consciousness only in the second half of this century. Leprosy is caused by a bacterium, Mycobacterium leprae, and progresses slowly, taking years to do its worst. Lassa fever is an acute hemorrhagic viral infection that runs its often lethal course in one to four weeks. Despite these substantial differences, the agents that cause these diseases share one unexpected and highly significant feature, according to a pair of papers in today's issue of Science.
Both M. leprae and Lassa fever virus (LFV) interact with the same receptor to gain access to the cells they infect. The common binding site is a membrane-associated protein named a-dystroglycan (a-DG). Together with a closely related protein, beta-dystroglycan (b-DG), a-DG links proteins associated with a cell's internal cytoskeleton with components of the matrix of materials that exists outside of cells, including one called laminin. Mutations affecting different components of this system in muscle cells have been linked to muscular dystrophies and peripheral neuropathies.
The dystroglycans are present in muscle, nerve and epithelial cells. "I thought it was interesting that two such totally different kinds of infectious agents have targeted this molecule [a-DG]. [But] I think there is nothing here but coincidence," said Patricia Spear, professor and chairman of microbiology-immunology at Northwestern University Medical School, in Chicago. Spear is the author of a "Perspective" article discussing the two papers. All three articles appear in the Dec. 11 issue of Science.
Could Help In Diagnostics Development
Michael Oldstone, head of the division of virology in the department of neuropharmacology at the Scripps Research Institute, in La Jolla, Calif., and his co-authors describe the interaction of LFV with a-DG in their paper, "Identification of a-Dystroglycan as a Receptor for Lymphocytic Choriomeningitis Virus and Lassa Fever Virus." Arenaviruses cause several types of hemorrhagic fevers. The authors show that four of them, including LFV and lymphocytic choriomeningitis virus (LCMV), bind directly to purified a-DG. Of the arenaviruses tested, only one, Guanarito, did not bind to the protein.
Oldstone and his collaborators found that binding to a-DG on mouse embryonic stem cells leads to entry of LCMV. The virus could not enter mutant cells that did not express a-DG. These mutant cells, however, became susceptible to virus infection if the membrane protein was reintroduced.
"This is the first time the receptor for the arenaviruses has been described," said Oldstone, who sees two potential therapeutic applications of the finding.
"If you solubilize the receptor, you can block arenavirus entry into cells and block infection. This offers the possibility of a therapeutic approach to block some of these lethal viruses for which there is now no satisfactory treatment," Oldstone told BioWorld Today.
Also, the reagents developed in the course of the research offer an opportunity for developing a diagnostic test for these hemorrhagic diseases. And for virologists, the finding may aid efforts to better classify hemorrhagic viruses and identify co-factors they use to enter cells and cause disease.
In the future, the Communicable Disease Center, in Atlanta, will use the reagents developed in this study to map the lethal arenaviruses which require the highest level of containment facility.
"We will also be looking at the precise region on the receptor molecule to which the virus binds, and determining if it is the same among different virus strains. Then, we will work toward purifying the receptor so we can do some structural studies on it," Oldstone said.
The same receptor figures prominently in a paper by Anura Rambukkana, an investigator at The Rockefeller University, in New York, and his co-authors, titled "Role of a-Dystroglycan as a Schwann Cell Receptor for Mycobacterium leprae." These researchers have shown that the leprosy bacillus binds to a protein in the extracellular matrix called laminin-2. This intermediary then binds to a-DG associated with rat and human Schwann cells, the specialized peripheral nervous system cells that support and insulate nerve fibers. Schwann cell destruction severely compromises the ability of nerves to function properly.
This finding, the first indication of a specific receptor used by the leprosy bacillus, provides significant insight into a disease that for centuries has generated fear and prejudice in the general population and disfigurement in infected individuals. The damage to peripheral nerves caused by leprosy bacilli can lead eventually to severe deformities.
Rambukkana, whose work is supported by the World Health Organization, is interested in preventing leprosy. He also sees implications for other diseases in this study.
"We are focusing on how we can prevent the damage to the nerve," Rambukkana said. "By doing that, we can also gain more insight into the early stages of other neurodegenerative diseases. Most of the nerve-damaging diseases have been implicated as immunologically mediated diseases. In my opinion, theimmunological part comes later in the disease process. The initial part is associated with non-immunological phenomena." *