Borna Disease Virus (Human)

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]

Computer-generated image of Borna Disease Virus. From: citizendium.org [2]

Etiology/Bacteriology

Taxonomy

Description

Borna disease virus (BDV) is a latent nonsegmented, negative-sense RNA virus with six identified open reading frames that produce proteins N, P, M, G, L and p 10. [3] BDV proteins may be glycosylated (M and G) or phosphorylated (P and L). The BDV genome is smaller than other negative -strand RNA viruses; and unlike other non-segmented, negative-strand RNA animal viruses, BDV replicates and transcribes in the nuclei of its hosts. It has distinguishable features, such as overlap of coding sequence, post-transcriptional modification properties, and alternative splicing in the nuclei of its host. It also has unique aspects of pathogenesis in that it is highly localized specifically in the central nervous system, has manipulation of activity-dependent synaptic plasticity, and has chronic persistence in the absence of overt inflammation and cytolysis. The BDV genome also has a degree of conservation with less than 6% divergence at the nucleotide level. [2] It reproduces in the host cell nucleus (only the negative-strand RNA viruses do so), and they primarily attack the older portion of the brain (the limbic system) and contribute to behavioral and mood alteration. (It is assumed that viral proteins disturb the neurotransmitter equilibrium). During infection, BDV influences the CNS in several ways: firstly a direct influence through binding of viral proteins with neurotransmitter receptors, and secondly an indirect influence through immune response and inflammatory reactions. Both types of mechanisms influence neurotransmission and lead to mood, behaviour and emotional changes in infected individuals and may be associated with human psychiatric disorders (affective disorders, addictions and psychotic disorders).[2] They remain the infected organism throughout their lifespan.

Historical Overview

BDV is among the oldest viruses and have been finding their way into our and our ancestors’ genetic material for at least 40 million years. Borna disease was first describe 200 years ago in southern Germany as a fatal neurologic disease of horses and sheep. Its name derived from the town Borna in Saxony, Germany, where a large number of horses died during an epidemic in 1885. [4]

Pathogenesis

Transmission/Reservoirs

Borna disease virus exists world-wide in horses, sheep, cattle, cats, dogs, and ostriches. [5] It is transmitted from animals to humans and between humans by infected saliva or other nasal mucosa secretions. This transmission through nasal, salival, or conjunctival secretions is currently assumed. [2]

Incubation/Colonization

It spreads trans-synaptically and intra-axonally towards olfactoric structures before moving onto the limbic system. [1] During the later onset of the infection, the Borna disease virus would diffuse throughout the central nervous system and can be detected in the peripheral nervous system. [1] Incubation period in humans is currently unknown, but is estimated to be around four weeks to a few months in horses and sheep.

Epidemiology

As documented in Germany and Australia, BDV is found in about one third (30%) of the adult population. The prevalence is about twice as high (60%) in children. Most of those infected (>80%) do not show any symptoms, and only 16-17% of those infected are predicted by some to form a mental illness during the course of his or her life. [6] In the overall population, it is estimated that 5% is at an increased risk of becoming ill. [6] Evidence of human BDV infection has been reported in the United States, Germany, and in other Eurasian continent, which includes Taiwan, Thailand, Iran and Japan. [3]

Virulence Factors

The proteins located on the BDV are demonstrated to represent the major antigenic components in BDV infection to which the humoral immune response is directed. [5] Proteins N, P, M, and G are the basis for the antigenicity of BDV. The matrix (M) protein is involved in virus attachment and aggregates to a tetrameric form by strong hydrophobic interactions. [5] The glycosylated (G) protein is also associated with the infectious particle, but N and P play principal roles in providing complex structures that give rise to a strong humoral immune response. [5]

Clinical Features

Medical conditions associated with significantly higher rate of active Bornavirus infection are acute depressive episodes (uni- and bipolar), in 80-90% of patients, chronic obsessive-compulsive disorders (OCD), in at least 50-60% of patients, and chronic fatigue syndrome (CFS/ME0 in at least 40% of patients. [6] The symptoms that are common to the majority of these patients are cognitive deficits and bradylogia (abnormally slow speech), reduced intellectual capability, attention and concentration deficits (especially among young adults and children), memory loss, and learning disabilities (especially among children and young adults). [6]

Diagnosis

Bornavirus infection can be diagnosed from a small blood sample (5-10 ml citrated blood or serum, children 1 ml) using special assays, such as ELISA formats. [6] A screen test measures Bornavirus-specific circulating immune complexes (CICs) consisting of viral proteins and the patient’s antibodies, detectable only once the virus has replicated. [6] For acute illness, it is necessary to also test for the viral proteins or antigens that signal an acute episode of viral activation with the CICs. [6] However, the presence of antibodies is not an indication of viral activity and a negative antibody test does not rule out the possibility of infection. [6]

Treatment

Patients diagnosed with BDV infection are treated with a drug that has been approved for the past 40 years for treatment of influenza A virus, which has the active ingredient of amantadine sulphate. [6] This has shown to be highly effective against natural Bornaviruses. Amantadine sulphate is a virostatic agent that inhibits virus replication, and, therefore, prevents the formation of harmful viral proteins. [6] Around 70-80% of patients infected with acute depression derive long-term benefits from amantadine sulphate, and it could be prescribed with antidepressants as well. [6]

Dosage level should be 2-4 mg of amantadine sulphate per day per kg of body weight. A patient who weighs 75 kg should take 150-300 mg of amantadine sulphate daily, and the initial dose of 1 mg of amantadine sulphate per kg of body weight for the first three or four days should be observed. [6]

Treatment duration should normally last up to 3 months, and clinical improvement are to be expected in the first month. During the first week, some restlessness and sleep disturbances are possible. [6]

Some studies have also found Ara-C (1-beta-arabinofuranosylcytosine) a drug often used in chemotherapy, to be effective in inhibiting the replication and spread of BDV. [2]

Prevention

Risk Factors

Significant risk factors include chronic stress and a weakened immune system. Chronic stress can be brought by a systematically over- or underdemanding work life, psychosocial stressors like unresolved conflicts, and poor coping strategies. A weakened immune systems from those medically induced (i.e. corticosteroid therapy) or as a result of illness increase the risk of virus activation. Patients with weakened immune systems that are especially at risk are adult oncology patients, patients with HIV, children with leukemia, and patients with autoimmune diseases. [2,6]

Prevention of a BDV infection is not easily prevented because transmission occurs early and unnoticed (generally transferred vertically from mother to child and horizontally through nasal secretions and saliva). In addition, there is a high prevalence of symptom-free carriers (30% adults and 60% children on average). [6] However, the disease could be prevented due to the ability to test increased risk from blood samples (high CIC values are an indicator), and prophylactic antiviral therapy is a short-term (4 weeks) option for patients in long-term care, and also for stressed healthy person with high CIC values ( and who do not respond to stress reduction). [6]

Host Immune Response

Encephalitic Borna Disease

Most of the morbidity and mortality following BDV infection stems from the host immune response to the virus and the continued immune-mediated death of infected and nearby uninfected cells rather than from direct virus-mediated lysis of infected cells. [3]

Behavioral Borna Disease

Immature central nervous system at the time of BDV infection shows cellular inflammation and abnormal levels of cytokines, chemokines, serotonin, norepinephrine, dopamine, and other neurotransmitters. [3]

References

for medical practitioners (family physicians, psychiatrists, pediatricians) and patients. Dr. Hanns Ludwig. Diamedis, 2010.]

Created by Amy Vu Student of Dr. Tyrrell Conway, University of Oklahoma