MECHANISMS OF MYCOPLASMA INDUCED ARTHRITIS

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Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that can bear a close histological resemblance to rheumatoid arthritis of humans. M. arthritidis-induced arthritis has been extensively studied as a model for arthritides caused by infectious agents and also as a model for examining the role(s) of superantigens in the development of autoimmunity. All strains of M. arthritidis are thought to produce the superantigen MAM, but many MAM-producing strains are relatively avirulent and factors other than MAM must be required for the development of arthritis. We have recently determined that one of these factors is the newly-discovered lysogenic bacteriophage MAV1. We have shown that avirulent strains of M. arthritidis become virulent when lysogenized with MAV1. MAV1 DNA integrates into the M. arthritidis chromosome at any of numerous sites, and the site of integration does not correlate with virulence. Therefore, the increase in virulence associated with MAV1 does not result from changes in regulation of chromosomal genes flanking MAV1 DNA inserts. Accordingly, we propose that MAV1 encodes a determinant that is involved with the development of arthritis. MAV1 is the first factor from any mycoplasma that has been shown to be associated with arthritis, and elucidation of this factor is important for fulfillment of the long-range goals of understanding the mechanisms of mycoplasma- induced arthritis and the role of phages as carriers of bacterial arthritogenic determinants. Factors analogous to the MAV1-encoded determinant may be prevalent in bacteria and mycoplasmas that cause arthritis in humans, and these factors may be important as vaccine candidates and as targets for drug design. The goal of the present proposal is to identify and characterize the MAV1-encoded determinant. Specific Aim 1 is to determine the complete nucleotide sequence of the 16 kb MAV1 DNA genome. By comparing the amino acid sequences of the predicted MAV1 gene products with those of the GenBank/EMBL databased, candidate MAV1 virulence determinants will be identified. Specific Aim 2 is to develop M. arthritidis gene transfer systems. Procedures for genetic transformation and vectors for transferring genetic material will be established. Specific Aim 3 is to evaluate the arthritogenic significance of the candidate virulence determinants. The candidate virulence determinants will be inserted into the M. arthritidis chromosome and/or specifically mutated to construct strains that will be examined for arthritogenicity in the rat model and used to conclusively identify the MAV1 genes that are involved in the development of arthritis.