Borna disease

Borna disease

R ROTT, S HERZOG AND J A RICHT

Introduction

Borna disease (BD) is a sporadically occurring, progressive viral polioencephalomyelitis predominantly affecting horses and sheep, more rarely other Equidae, cattle, goats, cats, dogs and rabbits, and, exceptionally, a variety of other species. After an incubation period of several weeks to many months locomotor and sensory dysfunctions occur followed by paralysis and death. Natural infections seem to be subclinical in most cases.11, 43 The causative agent, Borna disease virus (BDV), has recently been classified in a new family Bornaviridae.27

In Germany, where BD is endemic, it has been known for more than 250 years. The commonly used name ‘Bornasche Krankheit’ originated from the frequent outbreaks of the disease in the district of Borna in Saxony between 1894 and 1896. Borna disease has since been described in Switzerland in 1979,24 Japan, in 199710 and Austria in 199842 for the first time. It is uncertain whether clinically similar cases of equine encephalitides in France, Romania, Libya, and the Near East were in fact BD. The disease has not been diagnosed in southern Africa, but there is reason to believe that it is more widely distributed since virus-specific antibodies have been demonstrated in horses from several continents. 14

Detailed studies of the pathology of BD were conducted during the first decade of the twentieth century.17 In the late 1920s Zwick and co-workers44 established its viral aetiology by reproducing the disease with bacteria-free filtrates. More recently, a soluble, virus-specific intranuclear antigen has been shown to exist in brain material of infected animals.9, 37, 40 The causative virus has been propagated in cell cultures, 13, 23 its molecular structure characterized and its replication strategies determined,6, 35 while aspects of the pathogenesis of the disease have been elucidated.26, 38

Aetiology

Borna disease virus has been characterized as a spherical enveloped virus particle with a diameter of about 100 to 130 nm.19The viral genome consists of a non-segmented single-stranded, 8,9 kb large RNA of negative polarity with complementary 3’ and 5’ termini. The genomic organization with six major open reading frames (ORFs) is similar to that of other members of the order Mononegavirales. Therefore, BDV is classified by the international nomenclature commission of International Committee for the Taxonomy of Viruses (ICTV) as a prototype of the new family Bornaviridae containing only one genus, Bornavirus.27 Expression of the identified ORFs permitted identification and characterization of five BDV-specific proteins. The first open reading frame (ORF1) encodes a protein with a molecular weight of 38/39 kDa (p38, also known as p40), the putative nucleoprotein (N). The second open reading fram (ORF2) codes for a phosphorylated 24 kd protein (p24, also called p23), representing the putative phosphoprotein (P). The products of ORF1 and ORF2 (N and P) form a heterodimer as shown by coprecipitation with monoclonal antibodies and hybrid interaction studies. Recently, an additional open reading frame (ORFX1) has been identified which overlaps with ORF2, and encodes a non-glycosylated BDV protein designated p10 (also called X). The third open reading frame (ORF3) encodes a 16 kDa protein (p16) which is post-translationally glycosylated, resulting in a molecular weight of 18 kDa (gp18), which represents the putative membrane protein (M). The fourth open reading frame (ORF4) encodes a 57 kd protein (p57) which is highly N-glycosylated resulting in a molecular weight of 84 or 94 kDa (gp84 and gp94), representing the putative precursor glycoprotein (GP) of the virus; cleavage of this GP by the subtilisin-like cellular protease furin results in two fragments with molecular masses of approximately 48 kDa and 51 kDa.28 Finally, the gene product of ORF5 which is localized at the 3’ end of the cRNA has been identified very recently as a 190 kDa protein.41 Sequence homology with RNA-dependent RNA polymerases of other members of the order Mononegavirales or its nuclear localization in infected cells and its interaction with the RNA phosphoprotein indicate that ORF5 encodes for the BDV polymerase.41

Antigenic variants have been found using monoclonal antibodies.14, 30 Neutralizing antibodies are demonstrable, if at all, only in the late phase of infection,35, 39 and antigenic variants within one individual animal have not yet been observed.

Embryonic brain cells of various provenance can be infected with BDV and co-cultivation of infected brain cells with permanent cell lines of diverse, non-central nervous system (CNS) origin may result in persistent infection.13Virus produced in such cultures is cell-associated, spreads by cell-to-cell contact without the production of cytopathic effects. Borna disease virus obtained from persistently infected cells (e.g. BDV/MDCK cells) is capable of infecting ‘uninfected cultures’ of the same cell line without further co-cultivation.13 Infectious virus particles, virus-like structures and virus-specific proteins can be detected in such persistently infected MDCK cells.4, 9, 19, 30 Borna disease virus- specific proteins can be demonstrated in the nuclei or cytoplasm of infected cells by immunofluorescence with antibodies obtained from infected animals.13

Little is known about the consecutive steps involved in virus...

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