Spread of bovine herpesvirus type 5 (BHV-5) in the rabbit brain after intranasal inoculation

Following intranasal inoculation of wild-type BHV-5 in rabbits, we studied the sequential transneuronal passage of the virus in the CNS by immunocytoc hem istry, histopathology, and virus isolation. At 4 and 6 days postinfecti on (d.p.i,), rabbits had no or mild neurological signs, and virus was isola ted only from the olfactory bulbs. At 8 and 9 d.p.i., infected rabbits had severe neurological signs, and virus could be isolated from multiple region s of the brain segments, In these rabbits, high titers of virus were consis tently present in the anterior and posterior cortices, including frontal, p iriform/entorhinal, temporal, parietal, and occipital cortices, the hippoca mpus and the amygdala. Virus was isolated occasionally from the midbrain/di encephalon and pons/medulla. Virus was not isolated from the cerebellum and trigeminal ganglion of rabbits examined from 2-12 d.p.i. Immunocytochemist ry revealed virus-specific antigens at 4 d.p.i. within the glomerular layer , external plexiform layer, and mitral cell layer of the main olfactory bul b. At 6 d.p.i., virus-specific antigens were also present within the inner granular layer of the main olfactory bulb. At 8 and 9 d.p.i., widespread BH V-5-specific staining occurred in the areas of the brain connected to the m ain olfactory bulb, including the frontal/cingulate cortex, anterior olfact ory nucleus, lateral olfactory tubercle, piriform/entorhinal cortex, hippoc ampus, amygdala, dorsal raphe, and locus coeruleus. In the trigeminal gangl ion, specific staining tvas detected within a few neurons at 2, 4, 6, 8 d.p .i. However, further spread of the virus along the trigeminal pathway was n ot evident. These data indicate that BHV-5 replicates and spreads preferent ially in the olfactory pathway following intranasal instillation and that t his viral spread correlated with the severity of neurological symptoms and histopathological lesions.