Relapsing fever project
Borrelia hermsii in the blood of a patient with relapsing fever
Relapsing fever is caused by one of several different species of Borrelia, a group of spirochetes. Members of the genus Borrelia are parasites; they are not free-living. Borrelias are transmitted from one vertebrate to another by arthropods, usually ticks. Tick-borne relapsing fever occurs on most continents. In the U.S., it is most common west of the Mississippi River.
Relapsing fever takes its name from the characteristic recurrences of elevated temperatures and flu-like symptoms every few days. When the patient or a laboratory mouse has a fever, there are numerous spirochetes in the blood that can be detected by looking at a blood sample under the microscope. (The figure above shows a spirochete of the species Borrelia hermsii in the blood.) When the temperature is normal, spirochetes can't be seen in the blood. The disappearance of the spirochetes and the decline in the temperature correspond to the appearance in the blood of antibodies against the spirochetes.
The spirochetes avoid the immune response of the infected animal or person through antigenic variation. Essentially, the pathogen stays one step ahead of antibodies by changing its surface proteins. These surface proteins, called variable major proteins (VMP), are lipoproteins that have only 30-70% sequence in common. This amount of divergence in the amino acid sequence is sufficient to create a new antigenic "identity" for the organism. Antibodies in the blood that are binding to and clearing spirochetes expressing the old VMP do not recognize spirochetes expressing the new VMP. Cells expressing a new VMP spontaneously occur in the population at a frequency of 1/1,000 to 1/10,000. The antibodies to the old VMP apply a selection against cells expressing this VMP, thus, providing an opportunity for spirochetes expressing the new VMP to proliferate. Each cell has the potential for about 30-40 different VMP identities.
The main focus for this project in the laboratory has been the understanding the molecular mechanism for this antigen variation and determining the "rules of the game" between the pathogen and the host.
Antigenic variation is a common theme among pathogenic organisms. These include the agents of malaria, gonorrhea, and sleeping sickness. Important questions about antigenic variation are also relevant for such research areas as developing a vaccine against HIV, predicting the next influenza pandemic, and defining the specificity of the antibody (B-cell) response. Relapsing fever is a particularly good experimental model for studying antigenic variation in the laboratory, because the repertoire of variable genes and proteins is defined, animals can be infected with single cells, and the minimally effective immune response is IgM antibody. It is possible that the parameters of relapsing fever Borrelia infection can be well-enough defined that the infection can be simulated in most or all details in a computer, a first for an infectious disease.
Current areas of emphasis for the relapsing fever project in the laboratory are the following: (i) determination of the degree of site-specificity and of the biochemical mechanism of recombination involving the VMP genes; (ii) studies of molecular evolution of the VMP genes; and (iii) population biology and mathematical modeling of infection with and immune responses to the relapsing fever spirochetes under experimental and natural conditions.