This study describes the pathogenesis of the Ebola-Reston (EBO-R) subtype of Ebola virus for experimentally infected cynomolgus monkeys. The disease course of EBO-R in macaques was very similar to human disease and to experimental diseases in macaques following EBO-Zaire and EBO-Sudan infections. Cynomolgus monkeys infected with EBO-R in this experiment developed anorexia, occasional nasal discharge, and splenomegaly, petechial facial hemorrhages and severe subcutaneous hemorrhages in venipuncture sites, similar to human Ebola fever. Five of the six EBO-R infected monkeys died, 8 to 14 days after inoculation. One survived and developed high titered neutralizing antibodies specific for EBO-R. The five acutely ill monkeys shed infectious virus in various bodily secretions. Further, abundant virus was visualized in alveolar interstitial cells and free in the alveoli suggesting the potential for generating infectious aerosols. Thus, taking precautions against aerosol exposures to filovirus infected primates, including humans, seems prudent. This experiment demonstrated that EBO-R was lethal for macaques and was capable of initiating and sustaining the monkey epizootic. Further investigation of this animal model should facilitate development of effective immunization, treatment, and control strategies for Ebola hemorrhagic fever.

Experimental infection of cynomolgus macaques with Ebola-Reston filoviruses from the 1989-1990 U.S. epizootic.

Borna disease viruses (BDV) isolated from more than 20 naturally infected horses, 2 sheep and a possible feline isolate were included in these studies. Most of these wild-type viruses were grown in rabbit cells. Specifically rabbit-adapted viruses establish persistent infection in immortalized cell lines of various animal species. Brain-, tissue culture-, and cell-free released viruses could all be neutralized with antibodies from naturally and experimentally infected animals (horse; hamster, rat, rabbit, mouse, and chicken), with highest titres in birds. Splenectomized rabbits, which were subsequently infected with BDV, efficiently produced high titres of neutralizing antibodies. All of the neutralizing sera and cerebrospinal fluids from infected animals inhibited tissue culture spread of BDV. Experimental infection and hyperimmunization induced antibodies directed against the major components of the soluble antigen (60, 40/38, 25 and 14.5 kD proteins). Analysis of the s-antigen complex with these sera and 6 stable monoclonal antibodies revealed that it consists of 40/38 and 25 kD proteins. Although each of these antibodies detected intracellular virus-specific structures they did not recognize outer plasma membrane antigens, showed no cross-reactivity, and had no neutralizing capacity. Unifying pathogenetic concepts of this neurotropic virus and its structural elements are discussed.

Biology and neurobiology of Borna disease viruses (BDV), defined by antibodies, neutralizability and their pathogenic potential

Filoviruses are causative agents of a hemorrhagic fever in man with mortalities ranging from 22 to 88%. They are enveloped, nonsegmented negative-stranded RNA viruses and are separated into two types, Marburg and Ebola, which can be serologically, biochemically and genetically distinguished. In general, there is little genetic variability among viruses belonging to the Marburg type. The Ebola type, however, is subdivided into at least three distinct subtypes. Marburg virus was first isolated during an outbreak in Europe in 1967. Ebola virus emerged in 1976 as the causative agent of two simultaneous outbreaks in southern Sudan and northern Zaire. The reemergence of Ebola, subtype Zaire, in Kikwit 1995 caused a worldwide sensation, since it struck after a sensibilization on the danger of Ebola virus disease. Person-to-person transmission by intimate contact is the main route of infection, but transmission by droplets and small aerosols among infected individuals is discussed. The natural reservoir for filoviruses remains a mystery. Filoviruses are prime examples for emerging pathogens. Factors that may be involved in emergence are international commerce and travel, limited experience in diagnosis and case management, import of nonhuman primates, and the potential of filoviruses for rapid evolution.

Emerging and reemerging of filoviruses.

Borna disease represents a unique model of a virus-induced immunological disease of the brain. Naturally occurring in horses and sheep, the mechanisms of pathogenesis have been studied in experimental animals, namely in the rat. Many investigations have revealed that the infection of the natural hosts principally follows the same pathogenic pathways as observed in rats, leading to a severe encephalomyelitis. This affliction of the central nervous system results in severe neurological disorders that again, are fully comparable in laboratory animals to those in the natural and the different experimental hosts. In addition, alterations have been reported which are also based on the infection of the brain and do not result in the classical encephalitic clinical picture but rather in alterations of behavior. However, to all of our knowledge, the various clinical pictures of Borna disease are not caused by the infecting virus itself but rather by the hosts immune response towards it, i.e. by a virus-induced cell-mediated immunopathological reaction. The importance of virus-specific CD4+ T cells as exemplified by a cultured T cell line and of CD8+ T cells as shown by immunomodulatory substances and specific antibody treatment in vivo for the pathogenesis of acute Borna disease will be elucidated here. In addition, evidence will be provided that virus-specific CD8+ T cells are also responsible for the dramatic brain atrophy in the chronic phase of the disease in rats. Therefore, Borna disease not only lends itself exquisitely well to the study of the pathogenesis of an immunopathological disease of the brain but also represents one of the few models for immune-mediated tissue destruction that eventually leads to brain atrophy and clinically to dementia.

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Pathogenesis of Borna disease

Creutzfeldt-Jakob Disease after Administration of Human Growth Hormone

Unconventional Agents and Unclassified Viruses

Cowpox: a re-evaluation of the risks of human cowpox based on new epidemiological information.- Characterization of a cowpox-like orthopox virus which had caused a lethal infection in man.- Molecular genetic analyses of parapoxviruses pathogenic for humans.- Recent advances in molluscum contagiosum virus research.- Molecular anatomy of lymphocystis disease virus.- Detection of virus or virus specific nucleic acid in foodstuff or bioproducts - hazards and risk assessment.- Rapid molecular detection of microbial pathogens: breakthroughs and challenges.- Where do we stand with oral vaccination of foxes against rabies in Europe?.- Foot-and-mouth disease as zoonosis.- Molecular epidemiology of influenza.- Influenza virus: transmission between species and relevance to emergence of the next human pandemic.- Functional chimeric HN glycoproteins derived from Newcastle disease virus and human parainfluenza virus-3.- Viral factors determining rotavirus pathogenicity.- Viral zoonoses and food of animal origin: caliciviruses and human disease.- The role of human caliciviruses in epidemic gastroenteritis.- Clinical similarities and close genetic relationship of human and animal Borna disease virus.- Molecular characterization of Borna disease virus from naturally infected animals and possible links to human disorders.- Haemorrhagic fevers and ecological perturbations.- Transmission, species specificity, and pathogenicity of Aujeszky's disease virus.- The role of veterinary public health in the prevention of zoonoses.- Viral infections transmitted by food of animal origin: the present situation in the European Unio.- Viral zoonosis from the viewpoint of their epidemiological surveillance: tick-borne encephalitis as a model.- Strategies to avoid virus transmissions by biopharmaceutic products.

O.-R. Kaaden

Papers

Unconventional Agents and Unclassified Viruses

Viral zoonoses and food of animal origin : a re-evaluation of possible hazards for human health