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PubMed2006

Genetic variation at chemokine receptor CCR5 in leporids: alteration at the 2nd extracellular domain by gene conversion with CCR2 in Oryctolagus, but not in Sylvilagus and Lepus species.

Whereas in its natural host (Sylvilagus sps.) the effects of myxoma virus infections are benign, in European rabbit (Oryctolagus cuniculus), it causes a highly infectious disease with very high mortality rate, known as myxomatosis. There is evidence that, as with HIV-1 virus in human, myxoma virus may use chemokine receptors such as CCR5 of the host target cell for entry and activation of pathways of immune avoidance. We have characterized and compared CCR5 genes of leporid species with different susceptibility levels to myxomatosis. The CCR5 protein of O. cuniculus differs markedly from all those known from other species. The most striking was the replacement of a specific peptide motif of the second extracellular loop (ECL2) by a motif, which in other species characterizes the CCR2 molecules. While absent in Sylvilagus and Lepus species, this CCR2 imposed CCR5-ECL2 alteration was observed in all genomes of 25 European rabbits, representing the subspecies O. cuniculus algirus and O. cuniculus cuniculus. Allelic variation at the rabbit CCR5 locus confirmed that the gene conversion predates the subspecies split (1-2 Ma).

Alleles↗
PubMed1981

In vitro and in vivo inhibition of myxoma virus by treatment with phosphonoacetic acid.

Both myxoma and fibroma viruses were found to be sensitive in vitro to the effects of phosphonoacetic acid. Detectable myxoma virus replication was inhibited at a drug concentration of 100 micrograms/ml. Fibroma virus replication was inhibited at a concentration of 500 micrograms/ml. Because of this difference in sensitivity, myxoma virus was used to infect rabbits to test that efficacy of phosphonoacetic acid in the treatment of a systemic viral disease. Rabbits were given 400 mg kg-1 day-1 of phosphonoacetic acid subcutaneously in two injections. Phosphonoacetic acid-treated animals showed a reduction in the severity of disease. Neither serum viral antigen nor infectious virus could be detected. In phosphate buffered saline-treated animals both serum viral antigen and infectious virus were found. All animals treated with phosphate buffered saline died of myxomatosis.

Animals↗
PubMed2000

Infectious agents associated with rabbit pneumonia: isolation of amyxomatous myxoma virus strains.

Sixty-six rabbits, with no history of vaccination against myxomatosis and which had died of pulmonary lesions, were submitted for virological and serological tests for Myxoma virus (MV) infection and for bacteriological examinations. At post mortem, the diagnoses based on observed lesions were as follows: acute haemorrhagic pneumonia (38%); acute suppurative bronchopneumonia (35%); and fibrinohaemorrhagic bronchopneumonia with fibrinous pleuritis (27%). MV was isolated from 10% of the rabbits, mainly from those with acute haemorrhagic pneumonia. Serological evidence of MV infection was demonstrated in 44% of rabbits. Pathogenic bacteria species isolated from lungs were Pasteurella (spp. and multocida), Escherichia coli, Bordetella bronchiseptica and Pseudomonas aeruginosa, respectively, from 41, 11, 7 and 6% of samples. No relationship could be established between the presence of specific antibodies to MV and the observed pulmonary lesions or the results of the bacteriological examinations. A significant trend was established between the severity of the lesions and the results of the bacteriological examinations.

Animals↗
PubMed2000

Absence of a genetic bottleneck in a wild rabbit (Oryctolagus cuniculus) population exposed to a severe viral epizootic.

Infectious diseases and their demographic consequences are thought to influence the genetic diversity of populations. In Europe, during the last 50 years, the European rabbit (Oryctolagus cuniculus) has suffered two important viral epizootics: myxomatosis and rabbit viral haemorraghic disease (RVHD). Although mortality rates were very high, the impact of these diseases on genetic diversity has never been assessed directly. The subject of this paper is a wild rabbit population in France, which has been studied since the beginning of the 1980s. The first outbreak of RVHD occurred in 1995 and provoked a demographic crash. The population, sampled for the first time in 1982 and 1994, was sampled again at the end of 1996 to examine the impact of the epizootic on genetic diversity. In spite of the observed high mortality rate ( approximately 90%), analysis of 14 polymorphic loci (allozymes and microsatellites) showed no loss in genetic diversity after the epizootic. Determination of temporal changes in allele frequencies indicated that the population evolved under genetic drift. The temporal method of Waples demonstrated a significant decrease in the effective population size (Ne) correlated with the demographic crash due to the epizootic. However, the population had only been studied for two generations after the epizootic and the remnant population size probably stayed high enough ( approximately 50 individuals) to keep its genetic diversity at the precrash level. These results suggest that, contrary to what is usually thought and in spite of the subsequent high mortality rates, past epizootics (especially myxomatosis) may have had little effect on the genetic diversity of wild rabbit populations in Europe.

Alleles↗
PubMed1997

Interstitial orchitis with impaired steroidogenesis and spermatogenesis in the testes of rabbits infected with an attenuated strain of myxoma virus.

The pathogenesis of infertility associated with acute viral orchitis was investigated in a rabbit model. Infection of postpubertal male European rabbits with an attenuated strain of myxoma virus caused systemic disease with viral replication to high titres in the testes. Infected rabbits developed an interstitial orchitis and epididymitis. This was associated with degeneration of the seminiferous epithelium, decreased serum testosterone concentrations and increased serum LH concentrations. Virus was localized within the interstitial cells. Clearance of infectious virus from the testis occurred between day 20 and day 30 after infection, although viral DNA could still be detected by polymerase chain reaction at 120 days. Viral clearance was associated with a return to normal serum testosterone and LH concentrations. Anti-sperm antibodies were present in the serum as early as 5 days after infection and declined during the recovery phase. Rabbits were infertile at 60 days but returned to normal fertility 60-90 days after infection.

Animals↗
PubMed2001

Immunomodulatory proteins of myxoma virus.

Poxviruses collectively encode an impressive collection of diverse immunomodulatory proteins. In this review we draw attention to some of the new open reading frames (ORFs) discovered during the sequencing of the myxoma virus DNA genome [Cameron C, Hota-Mitchell S, Chen L, Barrett J, Cao J-X, Macaulay C, Willer D, Evans D, McFadden G (1999) The complete DNA sequence of myxoma virus. Virology 264:298-318] that may function to subvert the host immune system. Most of these predicted functions are speculative but some of the deduced primary amino acid sequences contain intriguing similarities to known cellular and viral proteins in the public domain for which immunomodulatory functions have been assigned.

Adjuvants, Immunologic↗
PubMed1993

Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits.

The epidermal growth factor (EGF) homologues encoded by vaccinia virus, myxoma virus, and malignant rabbit fibroma virus have been shown to contribute to the pathogenicity of virus infection upon inoculation of susceptible hosts. However, since the primary structures of these growth factors and the disease profiles induced by different poxvirus genera vary substantially, the degree to which the various EGF homologues perform similar roles in viral pathogenesis remains unclear. In order to determine whether different EGF-like growth factors can perform qualitatively similar functions in the induction of myxomatosis in rabbits, we created recombinant myxoma virus variants in which the native growth factor, myxoma growth factor (MGF), was disrupted and replaced with either vaccinia virus growth factor, Shope fibroma growth factor, or rat transforming growth factor alpha. Unlike the control virus containing an inactivated MGF gene, which caused marked attenuation of the disease syndrome and substantially less proliferation of the epithelial cell layers in the conjunctiva and respiratory tract, the recombinant myxoma virus strains expressing heterologous growth factors produced infections which were both clinically and histopathologically indistinguishable from wild-type myxomatosis. We conclude that these poxviral and cellular EGF-like growth factors, which are diverse with respect to primary structure and origin, have similar biological functions in the context of myxoma virus pathogenesis and are mitogenic for the same target cells.

Animals↗
PubMed1993

SERP1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation.

Myxoma virus is a leporipoxvirus that causes a rapidly lethal, generalized infection known as myxomatosis in the European rabbit (Oryctolagus cuniculus). A characteristic feature of myxomatosis is the specific downregulation of key pathways important for numerous host defenses against the viral infection. The SERP1 gene has significant sequence similarity to the serpin superfamily of serine proteinase inhibitors and is one of many virulence factor genes located within the terminal regions of the myxoma virus genome. Transcriptional analysis of the SERP1 gene in myxoma virus (strain Lausanne) indicates that it is expressed as a late gene and studies using a polyclonal anti-SERP1 antiserum indicate that it encodes a secreted protein with an apparent molecular weight of 55 kDa. Using myxoma virus and recombinant vaccinia virus constructs for experiments with tunicamycin and peptide N-glycosidase F, it is shown that the secreted SERP1 protein is modified by N-linked glycosylation. Mutation of both copies of the SERP1 gene in myxoma virus results in a significant attenuation of the virus, such that more than 50% of infected animals are able to recover from the otherwise lethal infection. Histological analyses of lesions taken from infected animals suggest that in the absence of the SERP1 protein, a more effective inflammatory response occurs, allowing a more rapid resolution of the infection. This suggests that SERP1 contributes to viral pathogenesis by interacting with cellular component(s) involved in the regulation of inflammation.

Animals↗
PubMed1996

Myxoma virus M-T7, a secreted homolog of the interferon-gamma receptor, is a critical virulence factor for the development of myxomatosis in European rabbits.

Myxoma virus is a leporipoxvirus of New World rabbits (Sylvilagus sp.) that induces a rapidly lethal infection known as myxomatosis in the European rabbit (Oryctolagus cuniculus). Like all poxviruses, myxoma virus encodes a plethora of proteins to circumvent or inhibit a variety of host antiviral immune mechanisms. M-T7, the most abundantly secreted protein of myxoma virus-infected cells, was originally identified as an interferon-gamma receptor homolog (Upton, Mossman, and McFadden, Science 258, 1369-1372, 1992). Here, we demonstrate that M-T7 is dispensable for virus replication in cultured cells but is a critical virulence factor for virus pathogenesis in European rabbits. Disruption of both copies of the M-T7 gene in myxoma virus was achieved by the deletion of 372 bp of M-T7 coding sequences, replacement with a selectable marker, p7.5Ecogpt, and selection of a recombinant virus (vMyxlac-T7gpt) resistant to mycophenolic acid. vMyxlac-T7gpt expressed no detectable M-T7 protein and infected cells supernatants were devoid of any detectable interferon-gamma binding activities. Immunohistochemical staining with anti-beta-galactosidase and anti-CD43 antibodies demonstrated that in vMyxlac-T7gpt-infected rabbits the loss of M-T7 not only caused a dramatic reduction in disease symptoms and viral dissemination to secondary sites, but also dramatically influenced host leukocyte behavior. Notably, primary lesions in wild-type virus infections were generally underlayed by large masses of inflammatory cells that did not effectively migrate into the dermal sites of viral replication, whereas in vMyxlac-T7gpt infections this apparent block to leukocyte influx was relieved. A second major phenotypic distinction noted for the M-T7 knockout virus was the extensive activation of lymphocytes in secondary immune organs, particularly the spleen and lymph nodes, by Day 4 of the infection. This is in stark contrast to infection by wild-type myxoma virus, which results in relatively little, if any, cellular activation of germinal centers of spleen and lymph node by Day 4. We conclude that M-T7 functions early in infection to (1) retard inflammatory cell migration into infected tissues and (2) disrupt the communication between sentinel immune cells at the site of primary virus infection in the subdermis and lymphocytes in the secondary lymphoid organs, thereby disabling the host from mounting an effective cellular immune response. To summarize, in addition to neutralizing host interferon-gamma at infected sites, we propose that M-T7 protein also modifies leukocyte traffic in the vicinity of virus lesions, thus effectively severing the link between antigen presenting cells of the infected tissue and the effector lymphocytes of the peripheral immune organs.

Animals↗
PubMed1997

The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes.

To investigate the contribution of the myxoma virus M-T4 gene to viral virulence, both copies of the M-T4 gene were inactivated by disruption and insertion of the Escherichia coli guanosine phosphoribosyltransferase gene. Infection of European rabbits with the recombinant M-T4-deleted virus, vMyxlacT4, resulted in disease attenuation. In contrast, infection of rabbits with vMyxlac elicited the classical features of lethal myxomatosis. A notable decrease in the number of secondary lesions in animals infected with vMyxlacT4 suggested an inability of the virus to disseminate in vivo. Infection of either a rabbit CD4+ T cell line, RL-5, or primary rabbit peripheral blood lymphocytes with vMyxlacT4- resulted in the rapid induction of apoptosis. Sequence analysis of M-T4 revealed both an N-terminal signal sequence and a C-terminal -RDEL sequence, suggesting that M-T4 resides in the endoplasmic reticulum. The M-T4 protein was found to be sensitive to endo H digestion and confocal fluorescence microscopy demonstrated that M-T4 colocalized with calreticulin, indicating that M-T4 is retained within the endoplasmic reticulum. Our results indicate that M-T4 is the first example of an intracellular virulence factor in myxoma virus that functions from within the endoplasmic reticulum and is necessary for the productive infection of lymphocytes.

Amino Acid Sequence↗
PubMed2000

Coevolution of host and virus: the pathogenesis of virulent and attenuated strains of myxoma virus in resistant and susceptible European rabbits.

Myxoma virus was introduced into the European rabbit population of Australia in 1950. Although the virus was initially highly lethal in rabbits, there was rapid selection for less virulent strains of virus and innately resistant rabbits. To investigate the basis of resistance to myxoma virus, we have compared the pathogensis of the virulent strain of myxoma virus originally released into Australia and an attenuated, naturally derived field strain of myxoma virus. This was done in laboratory rabbits, which have not been selected for resistance, and in wild rabbits that have developed significant resistance. Wild rabbits were able to recover from infection with virus that was always lethal in laboratory rabbits. Laboratory rabbits were able to control and recover from infection with attenuated virus. This virus caused a trivial disease in wild rabbits. There was little difference between laboratory and wild rabbits in titers of either virulent or attenuated virus in the skin at the inoculation site. However, resistant wild rabbits had a 10- to 100-fold lower titer of virulent virus within the lymph node draining the inoculation site and controlled virus replication in tissues distal to the draining lymph node. Replication of virus in lymphocytes or fibroblasts cultured from wild and laboratory rabbits demonstrated that resistance was not due to altered cellular permissivity for replication. Neutralizing antibodies were present in both susceptible and resistant rabbits, suggesting that these have no significant role in resistance. We hypothesise that resistance is due to an enhanced innate immune response that allows the rabbit to mount an effective cellular immune response.

Animals↗
PubMed1999

Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis.

Myxoma virus is a poxvirus that causes a virulent systemic disease called myxomatosis in European rabbits. Like many poxviruses, myxoma virus encodes a variety of secreted proteins that subvert the antiviral activities of host cytokines. It was recently demonstrated that the myxoma virus M-T1 glycoprotein is a member of a large poxvirus family of secreted proteins that bind CC-chemokines and inhibit their chemoattractant activities in vitro. To determine the biological role of M-T1 in contributing to myxoma virus virulence, we constructed a recombinant M-T1-deletion mutant virus that was defective in M-T1 expression. Here, we demonstrate that M-T1 is expressed continuously during the course of myxoma virus infection as a highly stable 43-kDa glycoprotein and is dispensable for virus replication in vitro. Deletion of M-T1 had no significant effects on disease progression or in the overall mortality rate of infected European rabbits but heightened the localized cellular inflammation in primary tissue sites during the initial 2 to 3 days of infection. In the absence of M-T1 expression, deep dermal tissues surrounding the primary site of virus inoculation showed a dramatic increase in infiltrating leukocytes, particularly monocytes/macrophages, but these phagocytes remained relatively ineffective at clearing virus infection, likely due to the concerted properties of other secreted myxoma virus proteins. We conclude that M-T1 inhibits the chemotactic signals required for the influx of monocytes/macrophages during the acute-phase response of myxoma virus infection in vivo, as predicted by its ability to bind and inhibit CC-chemokines in vitro.

Animals↗
PubMed1999

Role of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and viral pathogenesis.

The purpose of this study was to investigate the significance of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and role in viral virulence. To accomplish this, a recombinant myxoma virus was created in which the C-terminal RDEL motif of M-T4 was deleted and a selectable marker (Ecogpt) was inserted immediately downstream. We hypothesized that removal of the RDEL motif from M-T4 would alter the subcellular localization of the protein and provide insight into its antiapoptotic role. Surprisingly, removal of the RDEL motif from M-T4 did not affect localization of the protein within the endoplasmic reticulum (ER), but it did reduce the stability of the mutant protein. Pulse-chase immunoprecipitation and endoglycosidase H analysis coupled with confocal fluorescent light microscopy demonstrated that the M-T4 RDEL(-) mutant protein is retained in the ER like wildtype M-T4 and suggests that the C-terminal RDEL motif is not the sole determinant for M-T4 localization to the ER. Infection of cultured rabbit lymphocytes with the M-T4 RDEL(-) mutant virus results in an intermediate apoptosis phenotype compared with the wildtype and M-T4 knockout mutant viruses. A novel myxomatosis phenotype was observed in European rabbits when infected with the recombinant M-T4 RDEL(-) mutant virus. Rabbits infected with the M-T4 RDEL(-) virus on day 9 postinfection exhibited an exacerbated edematous and inflammatory response at secondary sites of infections, particularly the ears. Our results indicate that the C-terminal RDEL motif may not be solely responsible for retention of M-T4 to the ER and that M-T4 may have a dual function in protecting infected lymphocytes from apoptosis and in modulating the inflammatory response to virus infection.

Amino Acid Motifs↗