Vet Dermatol 2014; 25: 341–342
DOI: 10.1111/vde.12157
Editorial Orf Orf, contagious pustular dermatitis or contagious ecthyma, is a viral disease of sheep and goats that continues to present problems to farmers around the world. It is rarely fatal on its own, but rather presents a welfare problem to lambs and nursing ewes, often leaving them open to secondary bacterial infections. In rural Africa and Asia, it is considered one of the top 20 most important viral diseases for the subsistence farmer because it disrupts, amongst other things, the milking of sheep and goats through orf-induced mastitis. The virus is also zoonotic and considered an occupational hazard for farm workers and animal handlers; although the disease is restricted to localized lesions in most cases, more serious complications can occur.1 Orf is caused by a parapoxvirus closely related to the poxviruses that cause smallpox in humans and myxomatosis in rabbits, but unlike these diseases, control is more difficult to achieve through simple vaccination. The reasons for this are poorly understood, but the fact that natural infection does not preclude animals from re-infection indicates that sterile immunity through vaccination is unlikely to be achievable. Work by David McEwan Jenkinson et al. published in the early volumes of this journal, and celebrated in this 25th Anniversary issue, has provided insight as to why this might be the case. Jenkinson et al. were working in an era when little was known about the virus, but the attraction of working with orf was not only because it is an important disease for the farmer, but also because the disease is generally self-limiting and the virus could therefore be studied in a relatively straightforward manner in its natural host. Collectively, those early papers sought to describe the events happening in the skin in response to scarification and infection. It was clear from the outset that the response to viral infection appeared to be an enhanced form of the wound healing seen in response to scarification alone. The virus did not spread far from the site of infection, and it was proposed that this was due to the dense accumulation of MHC Class II+ dendritic cells, neutrophils and T cells that formed a network in the dermis underlying the infected epidermis. It was proposed that this formed a physical barrier that helped to contain the virus, stopping it from penetrating the dermis and, ultimately, exteriorizing it in the form of a scab.2 In one of their papers, Jenkinson et al. employed a fairly crude (by today’s standards) form of image analysis to demonstrate that viral antigen was detected only in the newly differentiated epidermis, spreading downwards from the cells immediately below the stratum corneum, but never penetrating the stratum basale or beyond. Lateral spread was also limited, but in this case it was less clear what the mechanisms for this might be.3 The finding that the viral antigen was only ever detected in the proliferating cells of © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 341–342.
the stratum spinosum pre-dated by some 4 years the report that orf virus encoded its own version of vascular endothelial growth factor (VEGF-E), which still more recently, has been demonstrated, in humans at least, to be involved in proliferation and migration of epidermal keratinocytes. In conclusion then, whilst it would appear that the virus uses the natural process of wound healing to allow it to replicate, it seems likely that the keratinocyte is the target cell for viral replication and that proliferating keratinocytes rather than cutaneous injury per se are required for an active infection. The recognition that orf virus is contained within the skin and that there is no evidence of a systemic phase to the infection might explain why the antibody response to the virus, which is clearly demonstrable, is thought not to be particularly important when immunity to infection is considered. This is in contrast to many of the other poxvirus infections, in which, although the route of infection may also be through the skin, spread of the virus to other organs can occur and is controlled partly by the antibody response. With the evidence that orf virus is contained locally in the skin, researchers went on to investigate whether topical application of a new generation of antiviral drugs, and in particular cidofovir, a nucleoside analogue of deoxycytidine monophosphate, could be used to treat the virusinduced skin lesions. Having first proved efficacy against orf virus in vitro, initial attempts to treat lesions in vivo with creams containing cidofovir (1–2% w/v) demonstrated that the excipient used to carry the active ingredient had contrasting influences on the outcome of treatment, either exacerbating the lesion or leading to its resolution. A successful follow-up was achieved using a spray of sucralphate gel, which has thixotropic properties (a gel at rest, but fluid when agitated), as the carrier. This not only removed the need for mechanical application of the active compound to the lesion, which may have been the cause of the variation in wound healing when the creams had been applied, but potentially also reduced the number of repeat applications of the drug.4 Cidofovir is, of course, not licensed for use as a treatment for orf in sheep and given its cost is never likely to be used universally, but the principle of successful treatment has been demonstrated, and its use to treat human orf lesions has grown in recent years. Twenty-five years on from these initial studies, we know much more about the virus and the genes that it encodes, including those that may be involved in promoting the inflammatory response that characterizes the lesion. The routine control of the disease in sheep and goats, however, remains problematical. Unlike other poxvirus infections where attenuated viruses can be used successfully as vaccines, protection against orf is best provided by fully virulent viruses,5 a vaccine strategy which inevitably results in outbreaks of disease caused by the vaccine itself. One key area of current research, 341
Editorial
however, makes use of the lack of sterile immunity in pre-exposed animals, so that the virus can act as a vaccine delivery vehicle for other pathogens. Although still at an early stage, proof-of-concept data have been obtained for orf-vectored vaccines against rabbit haemorrhagic disease virus, rabies virus and influenza A viruses, amongst others.6 Colin J. McInnes Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, EH26 0PZ, UK
References 1. Hosamani M, Scagliarini A, Bhanuprakash V, et al. Orf: an update on current research and future perspective. Expert Rev Anti-Infect Ther 2009; 7: 879–893.
342
2. Jenkinson DM, Hutchison G, Reid HW. The B and T cell responses to orf virus infection of ovine skin. Vet Dermatol 1992; 3: 57–64. 3. Jenkinson DM, McEwan PE, Moss VA, et al. Location and spread of orf virus antigen in infected ovine skin. Vet Dermatol 1990; 1: 189–195. 4. Sonvico S, Colombo G, Gallina L, et al. Treatment of orf virus infections in lambs using therapeutic paints of cydofovir/sucralfate gel combination administered topically by spraying. AAPS J 2009; 11: 242–249. 5. McInnes CJ, Wood AR, Nettleton PF, et al. Genomic comparison of an avirulent strain of ORF virus with that of a virulent wild type isolate reveals that the ORF virus G2L gene is non-essential for replication. Virus Genes 2001; 22: 141–150. 6. Rohde J, Amann R, Rziha HJ. New Orf virus (Parapoxvirus) recombinant expressing H5 hemagglutinin protects mice against H5N1 and H1N1 influenza A virus. PLoS ONE 2013; 8: e83802.
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 341–342.
DOI: 10.1111/vde.12157
Editorial Orf Orf, contagious pustular dermatitis or contagious ecthyma, is a viral disease of sheep and goats that continues to present problems to farmers around the world. It is rarely fatal on its own, but rather presents a welfare problem to lambs and nursing ewes, often leaving them open to secondary bacterial infections. In rural Africa and Asia, it is considered one of the top 20 most important viral diseases for the subsistence farmer because it disrupts, amongst other things, the milking of sheep and goats through orf-induced mastitis. The virus is also zoonotic and considered an occupational hazard for farm workers and animal handlers; although the disease is restricted to localized lesions in most cases, more serious complications can occur.1 Orf is caused by a parapoxvirus closely related to the poxviruses that cause smallpox in humans and myxomatosis in rabbits, but unlike these diseases, control is more difficult to achieve through simple vaccination. The reasons for this are poorly understood, but the fact that natural infection does not preclude animals from re-infection indicates that sterile immunity through vaccination is unlikely to be achievable. Work by David McEwan Jenkinson et al. published in the early volumes of this journal, and celebrated in this 25th Anniversary issue, has provided insight as to why this might be the case. Jenkinson et al. were working in an era when little was known about the virus, but the attraction of working with orf was not only because it is an important disease for the farmer, but also because the disease is generally self-limiting and the virus could therefore be studied in a relatively straightforward manner in its natural host. Collectively, those early papers sought to describe the events happening in the skin in response to scarification and infection. It was clear from the outset that the response to viral infection appeared to be an enhanced form of the wound healing seen in response to scarification alone. The virus did not spread far from the site of infection, and it was proposed that this was due to the dense accumulation of MHC Class II+ dendritic cells, neutrophils and T cells that formed a network in the dermis underlying the infected epidermis. It was proposed that this formed a physical barrier that helped to contain the virus, stopping it from penetrating the dermis and, ultimately, exteriorizing it in the form of a scab.2 In one of their papers, Jenkinson et al. employed a fairly crude (by today’s standards) form of image analysis to demonstrate that viral antigen was detected only in the newly differentiated epidermis, spreading downwards from the cells immediately below the stratum corneum, but never penetrating the stratum basale or beyond. Lateral spread was also limited, but in this case it was less clear what the mechanisms for this might be.3 The finding that the viral antigen was only ever detected in the proliferating cells of © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 341–342.
the stratum spinosum pre-dated by some 4 years the report that orf virus encoded its own version of vascular endothelial growth factor (VEGF-E), which still more recently, has been demonstrated, in humans at least, to be involved in proliferation and migration of epidermal keratinocytes. In conclusion then, whilst it would appear that the virus uses the natural process of wound healing to allow it to replicate, it seems likely that the keratinocyte is the target cell for viral replication and that proliferating keratinocytes rather than cutaneous injury per se are required for an active infection. The recognition that orf virus is contained within the skin and that there is no evidence of a systemic phase to the infection might explain why the antibody response to the virus, which is clearly demonstrable, is thought not to be particularly important when immunity to infection is considered. This is in contrast to many of the other poxvirus infections, in which, although the route of infection may also be through the skin, spread of the virus to other organs can occur and is controlled partly by the antibody response. With the evidence that orf virus is contained locally in the skin, researchers went on to investigate whether topical application of a new generation of antiviral drugs, and in particular cidofovir, a nucleoside analogue of deoxycytidine monophosphate, could be used to treat the virusinduced skin lesions. Having first proved efficacy against orf virus in vitro, initial attempts to treat lesions in vivo with creams containing cidofovir (1–2% w/v) demonstrated that the excipient used to carry the active ingredient had contrasting influences on the outcome of treatment, either exacerbating the lesion or leading to its resolution. A successful follow-up was achieved using a spray of sucralphate gel, which has thixotropic properties (a gel at rest, but fluid when agitated), as the carrier. This not only removed the need for mechanical application of the active compound to the lesion, which may have been the cause of the variation in wound healing when the creams had been applied, but potentially also reduced the number of repeat applications of the drug.4 Cidofovir is, of course, not licensed for use as a treatment for orf in sheep and given its cost is never likely to be used universally, but the principle of successful treatment has been demonstrated, and its use to treat human orf lesions has grown in recent years. Twenty-five years on from these initial studies, we know much more about the virus and the genes that it encodes, including those that may be involved in promoting the inflammatory response that characterizes the lesion. The routine control of the disease in sheep and goats, however, remains problematical. Unlike other poxvirus infections where attenuated viruses can be used successfully as vaccines, protection against orf is best provided by fully virulent viruses,5 a vaccine strategy which inevitably results in outbreaks of disease caused by the vaccine itself. One key area of current research, 341
Editorial
however, makes use of the lack of sterile immunity in pre-exposed animals, so that the virus can act as a vaccine delivery vehicle for other pathogens. Although still at an early stage, proof-of-concept data have been obtained for orf-vectored vaccines against rabbit haemorrhagic disease virus, rabies virus and influenza A viruses, amongst others.6 Colin J. McInnes Moredun Research Institute, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, EH26 0PZ, UK
References 1. Hosamani M, Scagliarini A, Bhanuprakash V, et al. Orf: an update on current research and future perspective. Expert Rev Anti-Infect Ther 2009; 7: 879–893.
342
2. Jenkinson DM, Hutchison G, Reid HW. The B and T cell responses to orf virus infection of ovine skin. Vet Dermatol 1992; 3: 57–64. 3. Jenkinson DM, McEwan PE, Moss VA, et al. Location and spread of orf virus antigen in infected ovine skin. Vet Dermatol 1990; 1: 189–195. 4. Sonvico S, Colombo G, Gallina L, et al. Treatment of orf virus infections in lambs using therapeutic paints of cydofovir/sucralfate gel combination administered topically by spraying. AAPS J 2009; 11: 242–249. 5. McInnes CJ, Wood AR, Nettleton PF, et al. Genomic comparison of an avirulent strain of ORF virus with that of a virulent wild type isolate reveals that the ORF virus G2L gene is non-essential for replication. Virus Genes 2001; 22: 141–150. 6. Rohde J, Amann R, Rziha HJ. New Orf virus (Parapoxvirus) recombinant expressing H5 hemagglutinin protects mice against H5N1 and H1N1 influenza A virus. PLoS ONE 2013; 8: e83802.
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 341–342.
