The Complete DNA Sequence of Myxoma Virus

Abstract

Myxomatosis in European rabbits is a severely debilitating disease characterized by profound systemic cellular immunosuppression and a high rate of mortality. The causative agent, myxoma virus, is a member of the poxvirus family and prototype of the Leporipoxvirus genus. As a major step toward defining the genetic strategies by which the virus circumvents host antiviral responses, the genomic DNA sequence of myxoma virus, strain Lausanne, was determined. A total of 171 open reading frames were assigned to cover the 161.8-kb genome, including two copies each of the 12 genes that map within the 11.5-kb terminal inverted repeats. Database searches revealed a central core of approximately 120 kb that encodes more than 100 genes that exhibit close relationships to the conserved genes of members of other poxvirus genera. Open reading frames with predicted signal sequences, localization motifs, or homology to known proteins with immunomodulatory or host-range functions were examined more extensively for predicted features such as hydrophobic regions, nucleic acid binding domains, ankyrin repeats, serpin signatures, lectin domains. and structural cysteine spacings. As a result, several novel, potentially immunomodulatory proteins have been identified, including a family with multiple ankyrin-repeat domains, an OX-2 like member of the neural cell adhesion molecule family, a third myxoma serpin, a putative chemokine receptor fragment, two natural killer receptor-like species, and a variety of species with domains closely related to diverse host immune regulatory proteins. Coupled with the genomic sequencing of the related leporipoxvirus Shope fibroma virus, this work affirms the existence of a conserved complement of poxvirus-specific core genes and expands the growing repertoire of virus genes that confer the unique capacity of each poxvirus family member to counter the immune responses of the infected host.

Myxoma virus in the European rabbit: interactions between the virus and its susceptible host

“…The sequence of MV revealed it to have 161.8 kB of DNA, encoding 171 unique genes [11]. The central portion of the genome encodes close to 100 genes that are among the highly conserved set of conserved poxviral genes, encoding mostly structural and housekeeping functions, while the ends have terminal inverted repeats (TIR) and closed hairpin looks at each end [32,34].…”

“…A number of features present in cellular CD200/OX-2 are also found in M141R, including the C-terminal transmembrane domain, two highly conserved cysteine residues involved in the formation of the V-like immunoglobin domain and several critical residues invariably conserved in immunoglobin domains [11]. An increased level of IFN-γ was observed when peripheral blood mononuclear cells purified from rabbits infected with MV deficient in the M141L gene (vMyx141KO) were activated in vitro [12].…”

“…The membrane-associated protein M128L of MV is 218 amino acids in length, predicted to have a molecular mass of 32 kDa and is predicted to function as an immunoregulator [11,13]. M128L shares significant amino acid homology to the cellular CD47 protein (integrin-associated protein, or IAP), a well documented regulator of the vertebrate immune response which exerts multiple functions on various immune cell types [99].…”

“…A number of key features present in CD47 proteins are also present in M128L, including an N-terminal signal sequence, a single predicted transmembrane domain and a short cytoplasmic tail [13]. The classical immunoglobulin-like domain is not predicted to be present in M128L; however, there is significant conservation of cystine residues and flanking amino acids that map to the CD47 immunoglobulin boundary domain [11]. M128L is fully dispensable for virus replication and infection in vitro and the vMyx128KO showed no obvious differences in growth or replication kinetics when compared to the wild-type MV [13].…”

“…The entire genome of myxoma virus strain Lausanne has been sequenced, and many of both the structural proteins and immunomodulatory proteins have been characterized [5,11]. There are many extensive and excellent reviews on the immunomodulatory proteins of poxviruses [42,50,64,69,74,75,87,91,106].…”