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Searching for molecular mimicry in Lentiviral diseases of sheep and goats

Davies, Janet Mary (1993) Searching for molecular mimicry in Lentiviral diseases of sheep and goats. PhD thesis, Murdoch University.

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Abstract

Molecular mimicry is the theory that an infectious agent such as a virus causes its pathology through mimicry of host cells at either the protein or nucleotide level. As lentiviral diseases have a protracted course of infection, differing breed susceptibilities and immune system involvement, it is possible that molecular mimicry contributes to their pathogenesis. The role of epitope mimicry, and mimicry of messenger RNA, in the development of the encephalitic condition in Visna infected sheep and the arthritic condition in caprine arthritis encephalitis virus (CAEV) infected goats was investigated.

Methods for searching for mimicry with computer programs (PASTA and BLAST) were investigated. Database searches revealed the problems with the current strategies such as the original application for which the software was designed and the comparison matrix by which sequences are examined. A new matrix from Tudos et al. (1990) was investigated using previously published data on the immunological effects of amino acid substitution in epitopes. This matrix was shown to be useful for inclusion in database searches aimed at finding epitope mimicry. Searching for messenger mimicry showed that nucleotide homology between unrelated sequences spanning 14, 15, 16 and 17 identical residues occur abundantly. One sequence of homology between the tether region of CAEV and human proteoglycan with 17 out of 18 identical nucleotides encoded peptides with 5 homologous amino acids. There was no antibody or T cell recognition of synthetic peptides encompassing this hit detectable in CAEV infected and arthritic goats.

Cross-reaction between sera raised in sheep against similar synthetic peptides of the Visna virus and 21.5kDa myelin basic protein (MBP) was demonstrated. Investigation of the responses of Visna infected sheep showed that only the MBP peptide and MBP, in some sheep, were recognised. The peptides elicited T cell responses from Lewis rats during EAE induced with Guinea pig MBP, but they were not immunogenic or encephalitic per se, nor able to induce T cell lines that transferred EAE. No T cell declined. response to the peptides was demonstrated in Visna sheep. It was concluded that epitope mimicry was not evident in the pathogenesis of the encephalitic condition of Visna.

Synovial antibody response to the envelope protein of CAEV has previously been shown to be important in the development of arthritis in CAEV infected goats. T ceil epitopes predicted from the surface protein of CAEV and their mimics identified by database searches did not evoke antibody or T cell responses from CAEV infected goats. It was found that the T cell responses of long term naturally infected goats to CAEV were slight and limited to 42% of goats.

The antibody response of CAEV infected goats to the transmembrane (TM) protein was demonstrated to be strongest in arthritic goats. An antigenic portion of this protein was amplified, cloned, expressed as a glutathione S-transferase fusion protein (GST-TM) and used to show that arthritic goats recognised this region. Antibodies from several arthritic goats that were affinity purified against the GST-TM protein reacted with the native CAEV TM protein but they did not cross-react with goat or horse proteoglycan, or cultured and fresh synovial membrane cell lysates or synovial fluid. Database searches with the antigenic region of the TM revealed a similar sequence with a 70kDa heat shock protein from Trypanosomes but there was no antibody recognition of synthetic peptides corresponding to this region. It was concluded that the response to the TM though it may be important in the development of arthritis, was not cross-reactive hence epitope mimicry was not demonstrated clinically.

From the computational based investigations it was clear that mimicry searching can reveal interesting sequence similarities but until the clinical immune response to these similar regions is determined, the pathogenic potential of the sequence similarity is not known. There are still short falls in computational approaches. The importance of finding the epitope and determining if there is a cross-reactive response clinically was considered crucial.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary Studies
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: repository@murdoch.edu.au. Thank you.
Supervisor(s): Carnegie, Patrick
URI: http://researchrepository.murdoch.edu.au/id/eprint/53036
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