Kinetics of virus spread and changes in levels of several cytokine mRNAs in the brain after intranasal infection of rats with Borna disease virus

Abstract

We have used the reverse transcriptase-polymerase chain reaction technique to gain insight into the pathogenesis of encephalitis caused by Borna disease virus (BDV). RNA specific for BDV was first detected in the olfactory bulb of intranasally infected rats at 6 days postinfection (p.i.). At 14 days p.i., high levels of BDV RNA were found in all brain regions, and at 26 days p.i., BDV-specific RNA was also present in the eye, nasal mucosa, and facial skin. In the chronic phase of the disease, BDV RNA was identffied in many peripheral organs but not in blood. Analysis of brain tissue for the presence of cytokine mRNAs revealed that the mRNA levels of interleukin-6 (IL-6), tumor necrosis factor alpha, and IL-lao had increased sharply at 14 and 26 days p.i. These cytokine mRNAs reached maximum levels at the peak of inflammatory reactions and decreased drastically in the chronic phase of the disease. Although IL-2 mRNA was also found in normal brain, it was markedly increased in BDV-infected brain at 14 days p.i. Expression of gamma interferon (IFN-y) mRNA, which was not observed in normal rat brain, was detected at 14 days p.i. and reached a maximum level at 38 days p.i. IL-2 and IFN-y mRNA expression correlated with expression of CD4 and CD8 mRNAs, indicating that both CD4+ and CD8+ T lymphocytes are induced in the early stages of BDV infection. Since IFN-,y and CD8 mRNA levels were still highly elevated in the chronic phase of Borna disease, it is likely that CD8+ T lymphocytes act to reduce inflammation and to ameliorate neurological signs during the chronic phase of infection.

A nose-brain pathway for psychotropic peptides: evidence from a brain evoked potential study with cholecystokinin

“…Several studies in rats have conclusively demonstrated a substantial brain uptake of radioactive labeled proteins, like horseradish peroxidase after application to the nasal or olfactory mucosa (Balin et al, 1986). Moreover, infections of brain tissue, like Borna disease (Shankar et al, 1992) and herpes simplex encephalitis (Eseri & Tomlinson, 1984;Stroop et al, 1984), may result from viruses entering the brain via the olfactory mucosa.…”

Intranasal administration of oxytocin: Behavioral and clinical effects, a review

“…Viruses have been widely used as transneuronal neuroanatomical tracers and interestingly for our present purpose many of them appear to infect the CNS via olfactory and/or trigeminal connections arising in the olfactory mucosa. Early investigations showed that a variety of viruses like Borna disease virus (Morales et al, 1988;Shankar et al, 1992), mouse hepatitis virus Barthold, 1988;Perlman et al, 1995), corona virus (Perlman et al, 1990) and mouse rabies virus (Lafay et al, 1991) enter the CNS along the olfactory pathways. Some recent additions are adenovirus type 1, flavivirus, lysosomal enzyme (Procario et al, 2012;Wolf et al, 2012;Yun et al, 2012), herpes simplex virus, entering also along the vomeronasal chemosensory system (Mori et al, 2005;Tomlinson and Esiri, 1983) and the human influenza virus (Majde et al, 2007).…”

Borna Disease Virus and the Brain

“…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. The pathway of dissemination of BDV following intranasal inoculation of the rat has been thoroughly analyzed [140,190]. The virus initially replicates in the neuroreceptor cells of the olfactory epithelium.…”

“…In the late stages of infection, BDV diffuses centrifugally, probably by using an anterograde axonal transport, and viral markers have been detected in peripheral nerves of all tissues and organs. Consequently, many tissues and organs become positive for viral markers [78,190,231]. These include lachrymal, salivary or sebaceous glands and, as a rule, any ectodermal/epithelial tissue that can be reached by BDV through central or peripheral innervation.…”

“…Proinflammatory cytokines including IL-1␣, TNF␣, and IL-6 can cause neuronal damage [118,171]. Levels of IL-6, TNF␣, and IL-1␣ mRNAs are significantly increased in BD rat brains and their expression correlates with the degree of inflammation and severity of neurological signs [190]. Moreover, production of IFN ␥ by infiltrating CD8 ϩ T-cells could induce MHC class II expression on astrocytes and microglia.…”