title: Genetic Variability of Myxoma Virus Genomes.
abstract: Myxomatosis is a recurrent problem on rabbit farms throughout Europe despite the success of vaccines. To identify gene variations of field and vaccine strains that may be responsible for changes in virulence, immunomodulation, and immunoprotection, the genomes of 6 myxoma virus (MYXV) strains were sequenced: German field isolates Munich-1, FLI-H, 2604, and 3207; vaccine strain MAV; and challenge strain ZA. The analyzed genomes ranged from 147.6 kb (strain MAV) to 161.8 kb (strain 3207). All sequences were affected by several mutations, covering 24 to 93 open reading frames (ORFs) and resulted in amino acid substitutions, insertions, or deletions. Only strains Munich-1 and MAV revealed the deletion of 10 ORFs (M007L to M015L) and 11 ORFs (M007L to M008.1L and M149R to M008.1R), respectively. Major differences were observed in the 27 immunomodulatory proteins encoded by MYXV. Compared to the reference strain Lausanne, strains FLI-H, 2604, 3207, and ZA showed the highest amino acid identity (>98.4%). In strains Munich-1 and MAV, deletion of 5 and 10 ORFs, respectively, was observed, encoding immunomodulatory proteins with ankyrin repeats or members of the family of serine protease inhibitors. Furthermore, putative immunodominant surface proteins with homology to vaccinia virus (VACV) were investigated in the sequenced strains. Only strain MAV revealed above-average frequencies of amino acid substitutions and frameshift mutations. Finally, we performed recombination analysis and found signs of recombination in vaccine strain MAV. Phylogenetic analysis showed a close relationship of strain MAV and the MSW strain of Californian MYXV. However, in a challenge model, strain MAV provided full protection against lethal challenges with strain ZA.
  
  
  
  Myxoma virus (MYXV) is pathogenic for European rabbits and two North American species. Due to sophisticated strategies in immune evasion and oncolysis, MYXV is an important model virus for immunological and pathological research. In its natural hosts, MYXV causes a benign infection, whereas in European rabbits, it causes the lethal disease myxomatosis. Since the introduction of MYXV into Australia and Europe for the biological control of European rabbits in the 1950s, a coevolution of host and pathogen has started, selecting for attenuated virus strains and increased resistance in rabbits. Evolution of viruses is a continuous process and influences the protective potential of vaccines. In our analyses, we sequenced 6 MYXV field, challenge, and vaccine strains. We focused on genes encoding proteins involved in virulence, host range, immunomodulation, and envelope composition. Genes affected most by mutations play a role in immunomodulation. However, attenuation cannot be linked to individual mutations or gene disruptions.
authors.affiliation: Department of Animal Sciences, Institute of Veterinary Medicine, Division of Microbiology and Animal Hygiene, Faculty of Agricultural Sciences, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Braun
authors.affiliation: Department of Genomic and Applied Microbiology and Göttingen Genomics Laboratory, Institute of Microbiology and Genetics, Georg August University, Göttingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thürmer
authors.affiliation: Department of Genomic and Applied Microbiology and Göttingen Genomics Laboratory, Institute of Microbiology and Genetics, Georg August University, Göttingen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Daniel
authors.affiliation: Department of Bioinformatics, Institute of Microbiology and Genetics, Georg August University, Göttingen, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Schultz
authors.affiliation: Institute for Mathematics and Informatics, University of Greifswald, Greifswald, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bulla
authors.affiliation: Institute of Diagnostic Virology, Friedrich Loeffler Institut, Greifswald-Insel Riems, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Schirrmeier
authors.affiliation: IDT Biologika GmbH, Dessau, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Mayer
authors.affiliation: IDT Biologika GmbH, Dessau, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubert
authors.affiliation: Department of Animal Sciences, Institute of Veterinary Medicine, Division of Microbiology and Animal Hygiene, Faculty of Agricultural Sciences, Georg August University Göttingen, Göttingen, Germany cczerny@gwdg.de.
authors.forename: Claus-Peter
authors.initials: CP
authors.lastname: Czerny
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017089:Ankyrin Repeat; D017209:Apoptosis; D002460:Cell Line; D002522:Chlorocebus aethiops; D019143:Evolution, Molecular; D014644:Genetic Variation; D016679:Genome, Viral; D023281:Genomics / Q000379:methods; D056747:Immunomodulation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D009233:Myxoma virus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D016366:Open Reading Frames; D010802:Phylogeny; D011213:Poxviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011817:Rabbits; D011971:Receptors, Immunologic; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology
chemical_list: D011971:Receptors, Immunologic; D014764:Viral Proteins; D014765:Viral Vaccines
keywords: DNA sequencing; genome analysis; myxoma virus; poxvirus