Feature

Out of the Mouths of Sheep

Scabby mouth virus, which affects sheep and people, is revealing some unexpected secrets.

By Dr Tony Robinson

If you drive around country roads in spring, you'll see groups of people standing around sheep yards surrounded by sheep, dust and din and doing indescribable things to lambs. Taking a good look, you might discern that one person is holding a pair of pliers and is slipping a rubber band over a lamb's tail or scrotum. Another is squirting something into its mouth with a drenching gun. A third is wielding what looks like a thick pencil and is vigorously scratching the inside of the lamb's hind leg. Most people will recognise docking and drenching, but what is scratching?

That person is vaccinating the lamb against scabby mouth, sometimes known as orf. This is a viral disease that usually affects lambs when they are a few months old, often causing massive scabbing around the mouth and severely affecting the lamb's growth. Although the main scabby mouth season is when the feed is getting low and the thistles are appearing, lambs are frequently affected in the first few weeks of life, making the vaccination at docking time too late. Infection is seen not only on the mouth of lambs, but also on their feet and on the ewe's udder. Occasionally, infection of the tongue is seen at slaughter, which precipitates a foot-and-mouth disease scare.

Scabby mouth is a very common disease in New Zealand, due to the intensive sheep-rearing practised in this country. It is controlled to some extent by vaccination, but this has its own problems. The scabby mouth vaccine is a living virulent virus, and the procedure is to give the lamb the disease on the leg to protect it from getting it on the mouth in later life. The down-side is that the use of fully virulent live virus in the vaccine ensures the perpetuation of the disease on the farm. The virus can survive for years in the scabs which fall off into sheep yards, and sheep camps are a source of infection for the next year's lamb crop. The choice is between having to vaccinate all lambs year after year or putting up with the losses caused by the naturally occurring disease.

Another problem with scabby mouth is that the virus infects people. It is not normally a serious disease, but nevertheless causes painful and unsightly lesions. These are frequently on the hands, but lesions on the face are not uncommon due to being butted by affected lambs during bottle feeding. These lesions take six weeks to heal.

More serious are infections in immunocompromised individuals, where a progressive disease producing so-called "giant orf" is seen. Immunodeficiency was once usually confined to those undergoing chemotherapy for neoplastic conditions, but now those with AIDS are another group at risk. There are many working days lost in the meat works due to infections on workers' hands combined with regulations preventing infected workers handling meat for human consumption.

Our group, supported by the Health Research Council of New Zealand, has been investigating this disease in both sheep and people. The main aim has been to look for alternative vaccines for sheep to reduce the level of infection on farms. Simple solutions to the problem that have worked for other viral vaccines have not worked for scabby mouth virus, and our approach has been to try to find out which parts of the virus are important in inducing a protective immune response and in virus virulence. If we can find the key components, then sub-unit vaccines or selective attenuation (weakening) of the virus should be possible.

Surprising Discovery

Arising from this work has been the surprising and exciting finding that the virus produces a protein that stimulates blood vessel growth. The protein is called vascular endothelial growth factor, and stimulates division of the cells lining blood vessels to form new vessels. It also makes the blood vessels leak, causing fluid to move out into the surrounding tissues.

The finding has provided an explanation for previous observations. Veterinarians, medical practitioners and pathologists have known for years that there is an enormous amount of swelling and reddening associated with infection with this virus, more than is seen with other viruses that affect the skin. This is particularly noticeable in human infections, where the tissues underlying the lesion can protrude at least a centimetre above the surrounding skin. The reason for this was not known and had been attributed to substances produced by the body in response to the infection. Instead, it turns out that the body is responding to a substance produced by the virus. It is the same substance that the body normally produces to stimulate its own blood vessels to grow.

How did the virus acquire this ability? It is generally accepted that viruses have evolved along with the host animals they infect, therefore the genes they contain probably have been captured from an ancestor many millions of years ago. Most of these viral genes have changed beyond recognition so that they show little resemblance to contemporary host genes. Some still retain similar functions despite the changes, but others have evolved to do other things.

A fascinating thing about the vascular endothelial growth factor gene in the virus is that it has not evolved very far from the gene of its host. The vascular endothelial growth factor genes studied so far have been found in humans, cattle, rats, mice and guinea pigs, and the gene in orf virus is very closely related to the one in cattle. Cattle and sheep genes are closely related, so it is likely that the gene has been derived from a sheep ancestor. Other evidence based on the structure of this gene and that of other strains of virus tells us that it has been acquired recently in evolutionary terms. We are witnessing evolution in action.

An immediate question is what advantage does this gene give to the virus? Why should it be important that the virus stimulate blood vessels to grow at the site of infection? We do not know, but can speculate. It could be an aid to survival by producing large amounts of exudate and scab for protection in the environment. Alternatively, the increased blood supply might cause increased numbers of skin cells in which the virus grows or an increased supply of essential chemicals needed for virus growth.

It was discovered a few years ago that other poxviruses, like the myxoma virus and vaccinia virus, produce a protein that causes epithelial skin cells to grow -- epithelial growth factor. These viruses do not have the vascular endothelial growth factor, nor does scabby mouth virus have epithelial growth factor. It looks as if scabby mouth has evolved its own unique strategy for survival. We believe that the endothelial growth factor will not be the only protein made by the virus to manipulate the host.

Scabby mouth virus is a member of the parapoxvirus group, which is in turn a member of the poxvirus family. Another parapoxvirus closely related to scabby mouth virus is a virus called pseudocowpox, harboured by cattle and causing milkers' nodules that appear on milkers' hands and arms. The changes caused by the virus at the site of infection are almost indistinguishable from that seen with scabby mouth virus. Similar viruses cause infections in seals, and all infect humans. Because they all cause a similar disease, we think it likely that the vascular endothelial growth factor gene is present in all these viruses. It also indicates that the gene was probably captured early in parapoxvirus evolution but after the divergence of parapoxviruses from the other poxviruses.

Can this discovery be turned to advantage? We are exploring the possibility of inactivating the growth factor gene to see if we can produce an attenuated vaccine. Another spin-off from this research is the possibility that the growth factor could be used in the pharmaceutical industry in wound healing.

Meanwhile, back on the farm, don't throw away the scratcher just yet. The existing vaccine will be around for a few years yet, but the secrets of scabby mouth virus are at last being revealed. The pieces of the puzzle are being put in place and we hope to use this knowledge to develop new and safer vaccines,

Dr Tony Robinson is a member of the Virus Research Unit at the University of Otago.