Bornaviruses of the order Mononegavirales, family Bornaviridae, are enveloped viruses with a non-segmented, negative-strand, 9 kb RNA genome. They are unique among RNA viruses in that they replicate within the nuclei of infected cells and employ RNA splicing machinery for their gene expression . They are highly cell associated and as a result, very few infectious particles are released from infected cells. Bornaviruses are probably transmitted between adjacent cells in the form of ribonucleoprotein complexes ).
Prior to 2008, the only known bornavirus was Borna Disease virus (BoDV-1). This causes lethal neurologic disease in horses, sheep and humans in Central Europe. Since then new mammalian bornaviruses have been isolated from horses (BoDV-2), and captive squirrels . Beginning in 2008, numerous bornaviruses have also been isolated from wild birds and bornaviral taxonomy has had to be revised significantly . While most of these avian bornaviruses infect psittacines, others infect canaries, finches and numerous waterfowl species [6, 7, 8]. Bornaviruses have also been isolated from snakes .
Mammalian bornaviruses cause a lethal meningoencephalitis in horses, sheep and humans as well as laboratory rodents. Avian bornaviruses also cause lethal disease in some species of birds but it has a very different clinical manifestation. For example, several species of Psittaciform 1 bornaviruses (PaBV) cause a unique neurologic and gastrointestinal disease. In these birds, the virus initially causes an immune-mediated encephalitis. The virus then spreads centrifugally along the cranial nerves and spinal cord to infect numerous other organs. Thus, invasion of the optic nerve can result in blindness. Invasion of the spinal cord can result in tremors, paralysis and ataxia. Invasion of the vagal nerve results in cardiac abnormalities and most notably, altered innervation of the anterior stomach – the proventriculus. This results in dilatation and eventual blockage of the proventriculus by accumulated food resulting in death by starvation. This Proventricular dilatation disease (PDD) was originally observed in large psittacines of the genus Ara and as a result was initially known as macaw wasting disease.
As its name suggests, PDD is characterized by massive distention of the avian proventriculus [10, 11]. This dilatation results from overfilling of the proventriculus due to its failure to empty into the ventriculus. As a result, it fills with undigested food. The proventricular wall becomes thin and atrophic to the extent that it may become translucent. Dilatation of other parts of the anterior gastrointestinal tract such as the crop, the ventriculus and the duodenum has also been reported.
One feature we have observed in experimentally infected cockatiels (Nymphicus hollandicus) is that the onset of clinical disease can be anticipated following a significant increase in the bird’s appetite. Animal keepers have reported voracious eating and on occasion, bird seeking to feed from a dish even before it has been placed in a cage (Turner D, Escandon P. Unpublished Observations). As a result, their food consumption increases significantly. This occurs two to three days prior to the onset of obvious proventricular dilatation. It is apparent that affected birds no longer receive satiation signals from the proventriculus. As a result, food intake increases at a time when the proventriculus is no longer capable of emptying. The proventriculus gets packed with food leading to blockage and eventual death as a result of starvation or secondary microbial infections.
While the natural route of PaBV infection is unknown, Leal et al  have tracked the spread of avian bornavirus from an injection site in the pectoral muscle through adjacent nerves, to the brachial plexus. It spreads from there into the thoracic spinal cord and thence to the brain. The virus subsequently spread from the brain to the ganglia in the gastrointestinal tract, the adrenal gland and the cardiac ganglia. Thus, the virus first targets the brain and central nervous system before spreading by way of nerves, most notably the vagal nerve, to other autonomic ganglia. Histologically, the primary disease lesions appear to occur within brain, the gastric plexus, the myenteric plexus in the proventricular wall and the celiac plexus. In these lesions, there appears to be a loss of neurons accompanied by a lymphocytic infiltration [13, 14].
Detailed studies on the location of brain lesions in experimentally infected cockatiels indicate that the virus is first detected in the thalamic nuclei and the hindbrain . The presence of detectable virus coincides with the development of an obvious lymphocytic encephalitis. While initially restricted to the central nuclei of the brain, by about day 60 post-challenge the virus spreads throughout both gray and white matter. This distribution of the virus and the lesions in birds are similar to those observed in naturally infected horses and sheep as well as experimentally infected mice. Thus Bornaviruses appear to have a predilection for the hippocampus, caudate nucleus, substantia nigra, the mid brain, and the hypothalamus .
Following the establishment of an encephalitis, the virus then spreads centrifugally  along the vagal nerve to the ganglia in the gastrointestinal tract, adrenal, heart, and kidneys. As a result, the neurons in the myenteric plexus are reduced in number and replaced with a lymphoplasmacytic infiltration [14, 16]. This plexus regulates gastrointestinal motility and smooth muscle contraction. While damage to the myenteric ganglion may contribute to the disease pathogenesis, the reduction in signaling does not appear to be sufficient to account for the gross dilatation of the proventriculus. Sectioning of the vagal nerve in birds, while slowing the passage of ingesta from the proventriculus into the ventriculus does not result in proventricular dilatation .
In an effort to further elucidate the pathogenesis of PDD in birds, preliminary transcriptome studies were performed in vitro on a human astrocytoma cell line that is readily infected by psittacine bornaviruses. As a result of these in vitro studies, our attention was drawn to a significant increase in transcription of neuropeptide Y. Neuropeptide Y is a major regulator of appetite and food intake. In order to follow up this observation, we performed transcriptome analysis on the brains of cockatiels experimentally challenged with avian bornavirus PaBV-2. They were humanely euthanized as they developed disease and their brains were assayed for RNA transcripts. The brains of four normal, uninfected cockatiels were analyzed at the same time. These confirmed the significant increase in NPY expression in infected birds. We suggest that this increase, together with myenteric ganglion damage, may explain the pathogenesis of proventricular dilatation disease.