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Volume: 27S3 • September 2001

Viral Hepatitis and Emerging Bloodborne Pathogens in Canada

Swine Viruses and Xenozoonosis*

Dongwan Yoo, Antonio Giulivi

Recent advances in xenotransplantation technology as a therapeutic approach have the potential to benefit human health. Liver cancer and liver cirrhosis in humans may some day be treated by implantation of porcine liver, diabetes may be treated by pancreatic cell transplantation, and neuronal tissues may be implanted for treatment of neurodegenerative diseases. As a source of donor organs, primates are widely considered unsuitable, mainly because of ethical issues and the likely transmission of infectious agents. Swine is the animal species of prime interest in clinical xenotransplantation. Pigs are easy to breed and economic to produce, and the physiology of swine is similar to that of humans.

Risks of xenotransplantation

It is important to recognize, however, that xenotransplantation may put the human community at risk. Transplantation of animal organs to humans will allow microorganisms present in the donor organs to bypass the normal defence mechanisms of the recipient. After transplantation, prolonged contact with the human body may allow the microorganisms to adapt and transmit to the recipient, and an agent that is non-pathogenic in its natural host may become pathogenic in the recipient. Immunosuppressive drug therapy is common in transplant patients, and the xenograft recipient's immune-suppressed condition may result in unpredicted consequences.

Of the many microorganisms infecting swine, viruses are the major concern, since other microorganisms can be greatly suppressed by routine treatment with antibiotics. Pathogens known to produce apparent disease in pigs should be the primary target to eliminate from donor herds. This is a relatively easy task, and therefore these pathogens are of less concern in xenotransplantation. In contrast, viruses that do not produce obvious disease in swine and those that result in latent infection are more difficult to eliminate and thus are of more concern, because xenotransplantation may provide unique opportunities for species jumping of viruses from pigs to humans. To date, about 25 different viruses have been identified in pigs. Most of these viruses do not cause apparent disease in humans, with the exception of Nipha virus, which caused recent outbreaks and deaths in Malaysia⁽¹⁾. Viruses with oncogenic potential, those that can be vertically transmitted, and those that are transmitted from semen are of particular concern and need to be carefully screened. Included in these categories are swine hepatitis E virus, porcine endogenous retrovirus, porcine cytomegalovirus, porcine circovirus types 1 and 2, and two newly identified herpesviruses⁽²⁾. With the exception of porcine circovirus type 2, all of these viruses are generally considered non-pathogenic in pigs.

Swine hepatitis E virus

Hepatitis E is one of several types of the recognized viral hepatitis in humans. Hepatitis E virus (HEV) is excreted in the feces of infected individuals, and contaminated feces are likely the primary source of transmission. The mortality rate is 1% to 3% but up to 20% higher among pregnant women⁽³⁾. Hepatitis E is traditionally found in countries where hygienic conditions are poor. In these countries two antigenic types of HEV, Asian type and Mexican type, have been recognized. A third type of human HEV has been isolated from HEV non-endemic countries, and this type appears to be distinct from the Asian or Mexican types.

Recently, an HEV-like virus has been discovered in swine and, surprisingly, this swine HEV appears to have remarkable similarity to the third type of human HEV⁽⁴⁾. The virus shows only a limited similarity to Asian or Mexican types. Evidence has accumulated indicating that swine HEV is likely a zoonotic agent and is able to infect primates and cause hepatitis⁽⁵⁾. Conversely, human HEV that is genetically similar to swine HEV infects pigs, but human HEV genetically distinct from swine HEV does not⁽⁶⁾. The transmission may occur by direct contact or through food or water contaminated with swine feces containing HEV. The cross-species infection from swine to humans may be dose-dependent.

The potential for cross-species infection by HEV raises a public health concern. Risk groups include swine practitioners, pig farmers and handlers, meat handlers, those involved in manure disposal, and others in close contact with swine. Since swine are of great interest for xenotransplantation, swine HEV is a major concern as a potential xenogeneic agent. Xenografts of swine organs to humans will allow the direct transmission of swine HEV. Although HEV infections in pigs and primates are asymptomatic⁽⁵⁾, it is not known whether the virus will become pathogenic in humans, especially immunosuppressed recipients. This virus should be considered as a potential xenogeneic agent.

Circoviruses

Circoviruses are frequently found in birds and plants, but pigs are the only mammalian species from which the virus has been isolated to date. In pigs, two types of circovirus have been identified, type 1 and type 2. Porcine circovirus type 1 is believed to be ubiquitous in pig populations worldwide, but there is no associated disease in pigs⁽⁷⁾. In contrast, type 2 circovirus, first recognized in Western Canada, has been suggested to cause a post-weaning multisystemic wasting syndrome in pigs⁽⁸⁾. Both types are closely related to each other but distinct. Type 2 circovirus is widespread throughout the world. Circovirus has the potential to transform primary porcine cells, but the potential risk for human transmission via xenotransplantation remains unclear. Circovirus-specific antibodies have been demonstrated in humans, mice, and cattle, but neither the virus nor the viral genome has been detected yet in any of these species but pigs. There is no evidence that humans have been infected with circovirus during normal contact with swine and swine products. It therefore remains unknown whether immunosuppressed xenograft recipients will be at risk of infection by porcine circovirus. Nevertheless, swine herds should be screened for the virus and positive herds excluded from the xenotransplantation protocols.

Herpesviruses

Herpesviruses are widespread in nature and found in insects, reptiles, amphibians, and every species of birds and mammals, including humans and primates. A hallmark of herpesvirus infection is that the virus remains persistent in the infected host for life and is frequently reactivated and shed. In pigs, four herpesviruses have been identified: pseudorabies virus, porcine cytomegalovirus, and two recently identified lymphotrophic herpesviruses. Pseudorabies virus is an important veterinary pathogen. However, Canada has remained free of pseudorabies for many years, and since the infection in pigs is clinically apparent, its xenogeneic risk is diminished and of less concern in xenotransplantation.

Porcine cytomegalovirus (CMV) causes rhinitis in young pigs, and in older pigs the infection is subclinical. Similar to human CMV, porcine CMV crosses the placenta and infects fetuses, with resulting congenital infections. Porcine CMV is endemic worldwide, including Canada⁽⁹⁾. Porcine CMV may be secreted into semen. The ability of porcine CMV to infect lung macrophages raises some concern that it may modify host defence mechanisms and alter the pathogenic consequences in the host. Further studies need to be done on the pathogenic potential of the porcine CMV in humans. Despite its potential importance for xenogeneic infection, little is known about porcine CMV pathogenesis and cell tropisms. No data are available on human exposure to the virus.

Besides pseudorabies virus and CMV, two additional herpesviruses have recently been identified in pigs. The two sequences for herpesvirus found in pig spleen⁽¹⁰⁾ were distinct from each other and furthermore were distinct from those of any known porcine herpesviruses sequences. The prevalence of the two new types is as high as 90% in domestic pigs. On the basis of the sequence information, these two new viruses have tentatively been designated porcine lymphotropic herpesvirus types 1 and 2⁽¹¹⁾. The viruses may replicate in lymphoblastoid cells with a specificity for either T or B lymphocytes. Despite the identification of the specific sequences, however, actual virus isolation has not yet been reported, and therefore their tropisms for other animal species, tissues, or lymphocytes are unclear.

Screening for swine viruses

Xenotransplantation may provide unique therapeutic benefits in modern medicine. A major concern, however, is the potential transmission of swine virus to humans and further transmission to the community from the xenograft recipient⁽²⁾. Therefore, viruses of concern need to be carefully screened. The list of tests available for known viruses in pigs should be comprehensive, and their sensitivity and specificity should be maximized. Research to detect unknown viruses of potential concern in xenotransplantation should be promoted. Development and use of animal models will provide the best opportunity to understand the basis for species jumping and viral pathogenesis. Policy development will be necessary to set up an appropriate national system for screening and monitoring animal sources and recipients for known viruses, discovery of new viruses, and development of new and better diagnostic methods. To provide reliable screening information, reference diagnostic laboratories need to be established for individual viruses. At a recent workshop organized by the Centre for Infectious Disease Prevention and Control of HC, general strategies for national surveillance and international coordination on xenotransplantation and xenozoonosis were discussed, and subsequently guidelines have been prepared. These guidelines will support the principles of xenogeneic safety with regard to individual and societal risks and benefits, as well as indicate future directions for xenotransplantation.

References

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2. Yoo D, Giulivi A. Xenotransplantation and the potential risk of xenogeneic transmission of porcine viruses. Can J Vet Res 2000;64;193-203.

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7. Tischer I, Mields W, Wolff D et al. Studies on epidemiology and pathogenicity of porcine circovirus. Arch Virol 1986;91:271-76.

8. Harding JSC, Clark EG. Recognizing and diagnosing post-weaning multisystemic wasting syndrome (PMWS). Swine Health Prod 1997:5:201-03.

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10. Ehlers B, Ulrich S, Goltz M. Detection of two novel porcine herpesviruses with high similarity to gammaherpesviruses. J Gen Virol 1999;80:971-78.

11. Ulrich S, Goltz M, Ehlers B. Characterization of the DNA polymerase loci of the novel porcine lymphotrophic herpesviruses 1 and 2 in domestic and feral pigs. J Gen Virol 1999; 80:3199-205.

* Parts of this article are reproduced, with the kind permission of the Canadian Veterinary Medical Association, from the following publication: Yoo D, Giulivi A. Xenotransplantation and the potential risk of xenogeneic transmission of porcine viruses. Can J Vet Res 2000;64:193-203.

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