. Lyme disease in humans is characterized by a variety of symptoms, experienced at different levels of severity. One of the most common symptoms of late stage disease is subacute recurring arthritis. In approximately 10% of untreated individuals this develops into chronic arthritis. The long term symptoms of Lyme disease reflect the persistent nature of infection with the causative agent, Borrelia burgdorferi. The murine model of Lyme disease allows the analysis of the immune response of inbred strains of mice developing severe, intermediate, or mild arthritis during infection with Borrelia burgdorferi. These mice reflect the spectrum of human Lyme arthritis and, therefore, provide a model to study the contribution of host genetic factors to pathological developments. Several characteristics have been associated with infection of C3H mice with Borrelia burgdorferi; severe arthritis, persistence of high levels of spirochetes in tissues, and intense systemic inflammatory activation. Infection of BALB/c mice is characterized by mild arthritis, and persistence of 10-fold fewer B. burgdorferi in tissues. This application proposes to map the genes responsible for these traits on the mouse chromosome. C3H and BALB/c mice will be mated, the F1 progeny backcrossed to the BALB/c parent, and the frequency of severe arthritis and high spirochete number in tissues of the backcrossed mice will be monitored. DNA prepared from backcrossed mice of known phenotypes for arthritis severity and persistence of high spirochete numbers will be subjected to polymerase chain reaction (PCR) amplification for detection of alleles of highly polymorphic markers of the mouse chromosome. This will allow association of particular alleles of C3H mice with the dominant phenotypes of severe arthritis and persistence of high numbers of spirochetes in the BC1 progeny. These polymorphic markers map to identified locations of the mouse chromosome and will allow assignment of the genes responsible for these traits to mouse linkage groups. The meiotic recombination frequency should allow sufficient chromosomal recombinants in the 400 BC1 mice to be analyzed to allow sub-chromosomal mapping of these traits. This information will be used in the construction of congenic mice, necessary for the confirmation of linkage of a particular trait to a DNA marker. These mice will also be crucial to the understanding of the genetic and biochemical elements involved in the pathophysiology of B. burgdorferi induced arthritis. Assignment of these genes within a mouse linkage group will suggest placement within a conserved linkage group in humans. Generation of polymorphic probes in the human will allow preliminary testing for association of alleles in humans suffering from severe Lyme arthritis.
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