MECHANISMS OF MYCOPLASMA-INDUCED ARTHRITIS

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DESCRIPTION ( applicant's abstract): Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that bears 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 an MAM must be required for the development of arthritis. One of these factors is the lysogenic bacteriophage MAV1. 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. We have proposed 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 goals of the present application are to identify and characterize the MAV1-encoded determinant and initiate studies to elucidate its function. From the nucleotide sequence of the 16-kb MAV1 genome, we have identified a candidate virulence determinant that is predicted to encode a membrane lipoprotein. Specific Aim 1 is to conclusively identify the particular MAV1 gene(s) associated with virulence of M. arthritidis. Specific Aim 2 is to determine whether the MAV1 virulence factor is a cytoplasmic or membrane protein and is produced in vivo. Specific Aim 3 is to explore the role of MAV1 in disease pathogenesis. How lysogenization of M. arthritidis by MAV1 affects the progression of arthritic disease will be examined. Through the use of immunocompromised animals, we will address the question of whether MAV1 contributes to the virulence of M. arthritidis by affecting interactions with host factors such as B and T cells and complement. Thus, the process of dissecting the function of MAV1 in virulence will be begun.