Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation

Abstract

Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.

Borna Disease Virus and the Brain

“…Adult rats infected intracerebrally or intranasally with BDV usually develop an immune-mediated biphasic behavioral disease. Rats display clinical signs and a histopathological picture very similar to that described for the naturally infected horse [36,38,39,90,150,151]. The onset of clinical signs, including movement abnormalities, aggressive and hyperactive behavior, coincides with the appearance of an inflammatory reaction in the brain that reaches its maximum of severity between days 30 and 40 after infection.…”

“…Nevertheless, the humoral response to BDV is not significantly impaired in PTI-NB rats [38,150]. Brains of PTI-NB rats harbor a viral load comparable to that found in rats with acute BD [36,88,150,207], illustrating the noncytolytic replication of BDV. Although PTI-NB rats do not show clinical signs, they exhibit distinct deficiencies in emotional and cognitive functions [9,57], as well as physiological and neurodevelopmental abnormalities [8,9].…”

“…Experimental infection of the rat has allowed the dissection of the dissemination pathway of BDV [36,140]. After initial replication in the neurons located at the site of entry, BDV likely migrates intraaxonally in an anterograde or retrograde direction towards the CNS.…”

“…Further spread is then possible into numerous diencephalic and telencephalic areas, through polysynaptic neuronal connections. Likewise, experimen- tal infection into the foot pad of a rat results in a retrograde transport of BDV, through the sciatic nerve, and then from neuron to neuron into the CNS [36]. Moreover, evidence of oral infection suggests that the nerve endings innervating intestinal regions are suitable for uptake of the virus and its transport to the CNS [130].…”

“…PBMC could have become infected during passage through the brain, or they may represent primary targets with the ability to spread the infection into the CNS, a situation that has been proposed for other neurotropic viruses [64,149]. Intravenous injection of rats with cell-free BDV is not followed by the establishment of a persistent infection [36]. This argues against cells within the PBMC being primary targets for BDV.…”