Introduction and history of foot-and-mouth disease virus.

Foot-and-mouth disease (FMD) has been recognized as a significant epidemic disease threatening the cattle industry since the sixteenth century, and in the late nineteenth century it was shown by Loeffler and Frosch to be caused by a submicroscopic, filterable transmissible agent, smaller than any known bacteria. The agent causing FMD was thus the first virus of vertebrates to be discovered, soon after the discovery of tobacco mosaic virus of plants. It was not until 1920 that a convenient animal model for the study of FMD virus was established by Waldmann and Pape, using guinea-pigs, and with the later development of in vitro cell culture systems for the virus, the chemical and physical properties of FMD virus were elucidated during the remainder of the twentieth century, culminating in 1989 with a complete description of the three-dimensional structure of the virion. FMD virus is classified as a species in the Aphthovirus genus of the family Picornaviridae. The virus is acid labile, and the genome RNA contains a characteristic tract of polyC located about 360 nucleotides from the 5' terminus. Seven main serotypes exist throughout the world, as well as numerous subtypes. The World Reference Laboratory for FMD is located at Pirbright, Surrey, UK and undertakes surveillance of FMD epidemics by serotyping as well as by genotyping isolates of the virus. A major epidemic of FMD occurred in the UK in 2001 and was caused by a virulent strain of FMD virus with origins in Asia. The advantages and some disadvantages of controlling FMD outbreaks by vaccination are discussed.

An approach to the control of disease transmission in pig-to-human xenotransplantation.

Although several major immunologic hurdles need to be overcome, the pig is currently considered the most likely source animal of cells, tissues and organs for transplantation into humans. Concerns have been raised with regard to the potential for the transfer of infectious agents with the transplanted organ to the human recipient. This risk is perceived to be increased as it is likely that the patient will be iatrogenically immunocompromised and the organ-source pig may be genetically engineered in such a way to render its organs particularly susceptible to infection with human viruses. Furthermore, the risk may not be restricted to the recipient, but may have consequences for the health of others in the community. The identification of porcine endogenous retroviruses and of hitherto unknown viruses have given rise to the most concern. We document here the agents we believe should be excluded from the organ-source pigs. We discuss the likelihood of achieving this aim and outline the potential means by which it may best be achieved.

Nipah virus: a recently emergent deadly paramyxovirus.

A paramyxovirus virus termed Nipah virus has been identified as the etiologic agent of an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore. The outbreak was first noted in late September 1998 and by mid-June 1999, more than 265 encephalitis cases, including 105 deaths, had been reported in Malaysia, and 11 cases of encephalitis or respiratory illness with one death had been reported in Singapore. Electron microscopic, serologic, and genetic studies indicate that this virus belongs to the family Paramyxoviridae and is most closely related to the recently discovered Hendra virus. We suggest that these two viruses are representative of a new genus within the family Paramyxoviridae. Like Hendra virus, Nipah virus is unusual among the paramyxoviruses in its ability to infect and cause potentially fatal disease in a number of host species, including humans.

Emerging zoonoses: crossing the species barrier.

The ability of infectious disease agents to cross the species barrier has long been recognised for many zoonotic diseases. New viral zoonotic diseases, such as acquired immune deficiency syndrome (AIDS), caused by human immunodeficiency viruses 1 or 2, emerged in the 1980s and 1990s, and have become established in the human population. Influenza virus continues to find new ways to move from avian species into humans. The filoviruses and the newer paramyxoviruses, Hendra and Nipah, highlight the increasing proclivity of some animal viral agents to infect human populations with devastating results. A previously unknown transmissible spongiform encephalopathy, bovine spongiform encephalopathy, has emerged in cattle in Europe and spread to humans as well as other animal species. A novel toxicosis, caused by Pfiesteria spp. dinoflagellates, has become a secondary problem in some areas where large fish kills have occurred. The increasing proximity of human and animal populations has led to the emergence of, or increase in, bacterial zoonoses such as plague, leptospirosis and ehrlichiosis. The factors which influence the ability of each infectious agent to effectively across the species barrier and infect new cells and populations are poorly understood. However, for all of these diseases, the underlying theme is the growth of the human population, the mobility of that population, and the efforts expended to keep that population nourished.

Zoonoses and haemorrhagic fever.

Virus zoonoses causing haemorrhagic fever have been recognized in three major families: Arenaviridae, Bunyaviridae and Filoviridae. All are negative-stranded RNA viruses, with genomes in two segments, three segments, or non-segmented, respectively. Acquisition of haemorrhagic fever in man generally requires close contact with a vertebrate vector species, usually rodents, for the arenaviruses and bunyaviruses. In the case of filoviruses, the vector is currently unknown, but these viruses may infect monkeys, and may contaminate cell cultures prepared from them. Both bunyavirus and arenavirus haemorrhagic fevers have arisen in humans following exposure to rodents, and in the case of Hantaan, a virus causing haemorrhagic fever with renal syndrome (HFRS), there have been numerous laboratory-acquired infections among animal care workers. As the technology to differentiate virus species has improved, it has become clear that there are numerous potentially hazardous viruses capable of causing HFRS or hantavirus pulmonary syndrome (HPS) within the feral rodent population. In many cases it would be desirable to introduce screening methods for such viruses before preparing cell cultures from these rodent or simian species that will be used to prepare biological products for human use.

The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.

In late 1994 and early 1995, Ebola (EBO) virus dramatically reemerged in Africa, causing human disease in the Ivory Coast and Zaire. Analysis of the entire glycoprotein genes of these viruses and those of other EBO virus subtypes has shown that the virion glycoprotein (130 kDa) is encoded in two reading frames, which are linked by transcriptional editing. This editing results in the addition of an extra nontemplated adenosine within a run of seven adenosines near the middle of the coding region. The primary gene product is a smaller (50-70 kDa), nonstructural, secreted glycoprotein, which is produced in large amounts and has an unknown function. Phylogenetic analysis indicates that EBO virus subtypes are genetically diverse and that the recent Ivory Coast isolate represents a new (fourth) subtype of EBO virus. In contrast, the EBO virus isolate from the 1995 outbreak in Kikwit, Zaire, is virtually identical to the virus that caused a similar epidemic in Yambuku, Zaire, almost 20 years earlier. This genetic stability may indicate that EBO viruses have coevolved with their natural reservoirs and do not change appreciably in the wild.