Borna virus infection

Edited April, 2017

These Guidelines were first published by Hans Lutz et al. in Journal of Feline Medicine and Surgery 17 (7), 2015, 614-616 and updated by Hans Lutz.

 

 

Synopsis

Borna disease virus (BDV) has a broad host range affecting primarily horses and sheep, but also cattle, ostriches, cats and dogs. In cats BDV may cause a non-suppurative meningoencephalomyelitis named “staggering disease”. The mode of transmission is not completely elucidated. Direct and indirect virus transmission is postulated, but BDV is obviously not readily transmitted between cats. Vectors such as ticks may play a role and shrews were identified as potential reservoir host. Access to forested areas was reported to be an important risk factor for staggering disease.

It is postulated that BDV may infect nerve endings in the oropharynx and spread via olfactory nerve cells to the CNS. A strong T-cell response may contribute to the development of clinical disease. Affected cats develop gait disturbances, ataxia, pain in the lower back and behavioural changes.

For diagnostic purposes detection of viral RNA by RT-PCR in samples collected from cats with clinical signs of Borna disease can be considered diagnostic. Serology is of little value, as on the one hand cats without signs of Borna disease may be seropositive and on the other hand not every cat with BDV infection has detectable levels of antibodies.

A hypothesis that BDV infection may be involved in the development of selected neurological disorders in man could not be confirmed. A research group within the German Robert Koch Institute studied the potential health threat of BDV to humans and concluded that BDV was not involved in the aetiology of human psychiatric diseases. However, the recent detection of a virus distantly related to BDV in 3 cases of fatal encephalitis suggests that the question of BDV involvement in neurologic disorders still cannot be clearly answered.

 

Fig. 1. On this cartoon of the map of Sweden, the shaded area shows the main location of feline staggering disease. Courtesy A.L. Lundgren, PhD thesis 1995

Fig. 1. On this cartoon of the map of Sweden, the shaded area shows the main location of feline staggering disease. Courtesy A.L. Lundgren, PhD thesis 1995

 

Introduction

 

Borna disease virus (BDV) historically affects horses and sheep (for review see Ludwig and Bode, 2000). The disease was first described in 1855 in horses which became severely sick, near the German town of Borna (cited in Lundgren et al., 1995). More recently, BDV has been described as the causative agent of a viral meningoencephalitis in cattle, ostriches, cats and dogs (Ludwig and Bode, 2000). In the mid-1970s, staggering disease – a non-suppurative meningoencephalomyelitis – was described in Swedish cats (cited in Cubitt and de la Torre, 1994 and Lundgren et al., 1995). Later, it was found that antibodies recognising BDV were common to these cases (Lundgren and Ludwig, 1993). Finally, in 1995, BDV was confirmed as the aetiological agent of staggering disease (Lundgren et al., 1995).

 

 

Virus

 

BDV is an enveloped virus with a helical capsid and a single-stranded RNA genome. The genome comprises 8,900 bases and, based on sequence analysis, it was assigned to the order of Mononegavirales as the only member of the Bornaviridae family (Cubitt and de la Torre, 1994; Cubitt et al., 1994). BDV particles are spherical and have an average diameter of approximately 100 nm. The genome encodes six known proteins including an envelope protein of 56 kd. Interestingly, BDV can infect a number of brain-derived cell types, but it does not usually induce any cytopathic effect.

 

 

Epidemiology

 

The mode of transmission of BDV has not been completely elucidated. It is postulated that transmission occurs through direct contact with an infected animal or indirectly by contact with secretions of an infected animal. In addition, the local occurrence of the disease in forested areas in Sweden suggests that vectors such as ticks may also play a role in transmission. In 2006, a shrew (Crocidura leucodon) was identified as the reservoir host in an area of Switzerland where BDV is prevalent in horses and sheep (Hilbe et al., 2006). These shrews have recently been shown to shed BDV over a period of over 200 days in urine, feces and saliva without showing clinical signs (Nobach et al., 2015). It is therefore clear that shrews can serve as reservoirs for BDV infection in cats. However, BDV infection appears not to be readily transmitted between cats.

Feline BDV has been reported in many countries, including Germany, Switzerland, Belgium, United Kingdom, Japan, Philippines, Indonesia, Australia and Finland (cited from Ludwig and Bode, 2000 and Someya et al., 2014). The fact that BDV was also shown to be present in horses in North America and several other species in Western China suggests that cats in the USA and China might also be affected by BDV. Clinical staggering disease has been mainly observed in Sweden, Austria, Germany, Switzerland and Liechtenstein.

 

The seroprevalence in cats with neurological diseases in different countries has been reported to vary widely between 0 and 67 %. In healthy cats, the occurrence of BDV antibodies is much lower, varying between 2 and over 40 % (Reeves et al., 1998). Access to forested areas was reported to be an important risk factor for staggering disease, since 68 % of all clinical cases occurred in cats with access to forests. Staggering disease shows a clear peak in frequency in the spring (Lundgren, 1992). So far, an association between BDV infection and gender has not been described. The findings on the age distribution of BDV infection are controversial. A recent study in Japan found no age preference in BDV infection although cats younger than one year were already found to be affected (Someya et al., 2014).

Borna Lundgren diss Fig. 2 major clinical findings

(Courtesy A.L. Lundgren, PhD thesis1995)

 

 

Pathogenesis and clinical signs

 

It is postulated that BDV may infect nerve endings in the oropharynx, the nose and/or the intestinal tract. The virus is thought to migrate along the nerves to the central nervous system (CNS) (Wensman et al., 2014), where it leads to lymphocytic inflammation and neuronal degeneration. A strong T-cell response to the virus is believed to be responsible for the development of clinical signs, but other factors may also be important for disease development (Wensman et al., 2014). Affected cats develop gait disturbances, ataxia, pain in the lower back and behavioural changes. In some cases, the affected cats lose the capacity to retract their claws. Clinical signs will usually progress and affected cats will eventually die after developing severe paralysis of the hind legs. However, some cats will recover partially or even completely. Subclinical infections can also occur.

 

Borna Lundgren diss Fig. 3a clincal cat.

Fig. 3 One-year old female domestic shorthair with typical clinical signs of staggering disease. Courtesy A.L. Lundgren, PhD thesis 1995

 

 

Immune response

 

CD8+ lymphocytes stimulated by BDV have been found in peripheral blood, spleen and brain (Johansson et al., 2002). These findings suggest that a successful immune reaction usually allows infected cats to control the infection. A weak innate immune response to BDV infection in rat brain cell cultures was recently described (Lin et al., 2013). It is therefore to be expected that a weak innate immune response may also contribute to disease development in cats.

 

 

Diagnosis

 

Diagnosis on the basis of clinical signs alone is not possible as there are several other viral infections that can lead to similar clinical signs (Feline Immunodeficiency Virus, Feline Leukaemia Virus and Feline Coronavirus). Detection of antibodies to BDV by ELISA or indirect immunofluorescence in cats exhibiting clinical signs typical for BDV infection permit a tentative diagnosis (Wensman et al., 2012).

However, the diagnostic sensitivity of the detection of antibodies, at 81 %, means that not every cat with BDV infection will have detectable levels of antibodies (Wensman et al., 2012). The reason for this is unclear. It is speculated that different strains of BDV exist which are sufficiently different from the antigen used in the assay and therefore remain undetected. Alternatively, some cats may not be capable of mounting an immune response that is serologically detectable.

The diagnostic specificity of antibody detection is also very low, as many seropositive cats may be completely healthy (Wensman et al., 2012). In the absence of clinical signs of Borna disease, diagnostic serology is of little value.

Detection of viral RNA by RT-PCR (reverse transcription PCR) in pooled samples of blood, serum, urine, conjunctival, nasal, oral and anal swabs collected from cats with clinical signs of Borna disease can be considered diagnostic (Wensman et al., 2012).

Currently, the most reliable means of diagnosis of Borna disease is considered to be pathology and histopathology. Immunohistochemistry or detection of BDV-RNA are techniques that confirm a tentative diagnosis of BDV infection. However, they are not used in routine diagnosis as they are expensive and require experience. Additionally not all clinically affected cats are positive by these tests.

 

 

Zoonotic aspects

 

As BDV persistently infects the central nervous system of many animal species, it was postulated that this virus might also infect humans. Indeed, it was shown that humans can be seropositive for BDV and that the frequency of BDV antibodies was increased in human patients with chronic neurologic disorders. Specifically, among 70 psychiatric patients, 20 % were found to be seropositive, compared to a few percentage points of the normal population. This led to the hypothesis that BDV infection may be involved in the development of selected neurological disorders (Bode et al., 1993; Bode and Ludwig, 2003) and triggered the creation of a research group within the German Robert Koch Institute in the 1990s to study the potential health threat of BDV to humans. In 2007, this research group published a statement that

1) the methods providing seropositive results in human blood were not adequate to support a reliable statement about the presence of antibodies to BDV and

2) that the RNA sequences found in human blood and tissue were the consequence of BDV contamination in the laboratory of the respective research lab.

Therefore, it was concluded that BDV was not involved in the aetiology of human psychiatric diseases and after dozens of careful studies the research group ended its activity.

For details, see:

http://www.rki.de/DE/Content/Forsch/Forschungsschwerpunkte/NeueRisiken/NeuartigeErreger/Einstellung_Projekt_Bornavirus.html.

However, a study published in 2016 demonstrated that patients with primary psychosis showed significantly more frequently circulating immunecomplexes and BDV antigen in blood than in blood samples of healthy donors. The authors concluded that surveillance of BDV should be considered in psychiatric research (Zaliunaite et al., 2016). Furthermore, 3 breeders of variegated squirrels (Sciurus variegatoides) in Germany independently developed encephalitis and died within 2 to 4 months after the onset of clinical signs. Using advanced molecular procedures, researchers at the Friedrich-Löffler-Institute in Greifswald and the Bernhard Nocht Institute for Tropical medicine, Hamburg, detected a previously unknown bornavirus in brain samples of the 3 patients and in a contact squirrel (Hoffmann et al., 2015). This virus was designated variegated squirrel bornavirus 1 (VSBV-1). A publication of 2017 found among more than 450 squirrels from Germany, the Netherlands and the United Kingdom VSBV-1 RNA in 11 squirrels belonging to 2 squirrel species (Schlottau et al., 2017). These observations suggest that handling these animals by humans represents a considerable risk for transmission. Whether or not cats may become infected by VSBV-1 is not clear yet.

 

 

Borna Lundgren diss Fig. 3b mononuclear adventitial cuffs, microgliosis.

Perivascular mononuclear cuffs in the caudal colliculus. Courtesy A.L. Lundgren, PhD thesis1995

 

Pathology

 

In cats with end-stage staggering disease, mild neutropenia is observed in about a third of the affected population. No other changes of clinical or biochemical parameters are observed. The most important histopathological findings include perivascular cuffing in the hippocampus, basal ganglia, cerebellum, cerebrum and the grey matter of the brain stem (Lundgren, 1992). In addition, plasma cells were frequently seen in the close vicinity of neurons (Lundgren et al., 1997), indicative of an inflammatory reaction and thereby explaining the clinical findings in cats with staggering disease.

 

Borna Lundgren diss Fig. 3c antigen in neuron, pons.Borna Lundgren diss Fig. 3d RNA in neuron, in situ hybrid

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Prevention

 

Currently, no vaccine is available for the prevention of staggering disease. As the exact modes of transmission are still not completely clear, it is difficult to make specific recommendations for preventive measures. Cats without access to a rural environment are probably at a lower risk of BDV infection compared to those with unlimited access to such areas. In areas where staggering disease is known to occur, it might therefore be recommended that cats should be kept indoors. However, limiting outdoor access should be carefully weighed against the risk of BDV infection. For many cats, outdoor access is an important component of their well-being.

 

 

Key points

 

  • Borna disease virus is the aetiological agent of staggering disease seen in several animal species, including horses, sheep and cats.
  • Transmission probably occurs through direct contact or indirectly via the secretions of an infected animal.
  • Ticks and shrews may play a role in transmission.
  • Infection starts in the olfactory nerve cells and then spreads to the CNS.
  • Signs include abnormal gait, ataxia progressing to paralysis, lower back pain and behavioural changes.
  • Serological tests are of little diagnostic value.
  • Detection of viral RNA by RT-PCR in pooled samples of blood and body secretions are diagnostic for the infection.
  • Pathology and histopathology, in conjunction with clinical signs, are considered the most reliable diagnostic methods.
  • BDV is so far not known to be involved in the aetiology of psychiatric disease in humans.
  • Other Bornaviruses such as the VSBV-1 may represent a risk for humans.

 

References

 

Bode L, Ferszt R, Czech G (1993). Borna disease virus infection and affective disorders in man. Arch Virol Suppl 7: 159-167.

Bode L, Ludwig H (2003). Borna disease virus infection, a human mental-health risk. Clin Microbiol Rev 16: 534-545.

Cubitt B, de la Torre JC (1994). Borna disease virus (BDV), a nonsegmented RNA virus, replicates in the nuclei of infected cells where infectious BDV ribonucleoproteins are present. J Virol 68: 1371-1381.

Cubitt B, Oldstone C, de la Torre JC (1994). Sequence and genome organization of Borna disease virus. J Virol 68: 1382-1396.

Hilbe M, Herrsche R, Kolodziejek J, Nowotny N, Zlinszky K, Ehrensperger F (2006). Shrews as reservoir hosts of borna disease virus. Emerg Infect Dis 12: 675-677.

Hoffmann B, Tappe D, Hoper D, Herden C, Boldt A, Mawrin C, Niederstrasser O, Muller T, Jenckel M, van der Grinten E, Lutter C, Abendroth B, Teifke JP, Cadar D, Schmidt-Chanasit J, Ulrich RG, Beer M (2015). A Variegated Squirrel Bornavirus Associated with Fatal Human Encephalitis. N Engl J Med 373:154-162.

Johansson M, Berg M, Berg AL (2002). Humoral immune response against Borna disease virus (BDV) in experimentally and naturally infected cats. Vet Immunol Immunopathol 90: 23-33.

Lin CC, Wu YJ, Heimrich B, Schwemmle M (2013). Absence of a robust innate immune response in rat neurons facilitates persistent infection of Borna disease virus in neuronal tissue. Cell Mol Life Sci 70: 4399-4410.

Ludwig H, Bode L (2000). Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology. Rev Sci Tech 19: 259-288.

Lundgren AL (1992). Feline non-suppurative meningoencephalomyelitis. A clinical and pathological study. J Comp Pathol 107: 411-425.

Lundgren AL, Johannisson A, Zimmermann W, Bode L, Rozell B, Muluneh A, et al (1997). Neurological disease and encephalitis in cats experimentally infected with Borna disease virus. Acta Neuropathol 93: 391-401.

Lundgren AL, Ludwig H (1993). Clinically diseased cats with non-suppurative meningoencephalomyelitis have Borna disease virus-specific antibodies. Acta Vet Scand 34: 101-103.

Lundgren AL, Zimmermann W, Bode L, Czech G, Gosztonyi G, Lindberg R, et al (1995). Staggering disease in cats: isolation and characterization of the feline Borna  disease virus. J Gen Virol 76: 2215-2222.

Nobach D, Bourg M, Herzog S, Lange-Herbst H, Encarnacao JA, Eickmann M, Herden C, (2015). Shedding of Infectious Borna Disease Virus-1 in Living Bicolored White-Toothed Shrews. PloS one 10:e0137018.

Reeves NA, Helps CR, Gunn-Moore DA, Blundell C, Finnemore PL, Pearson GR, et al (1998). Natural Borna disease virus infection in cats in the United Kingdom. Vet Rec 143: 523-526.

Schlottau K, Jenckel M, van den Brand J, Fast C, Herden C, Hoper D, Homeier-Bachmann T, Thielebein J, Mensing N, Diender B, Hoffmann D, Ulrich RG, Mettenleiter TC, Koopmans M, Tappe D, Schmidt-Chanasit J, Reusken CB, Beer M, Hoffmann B (2017). Variegated Squirrel Bornavirus 1 in Squirrels, Germany and the Netherlands, Emerg infect dis 23: 477-481.

Someya A, Fukushima R, Yoshida M, Tanahashi Y, Prapeuk T, Iizuka R, et al (2014). A Study on Borna Disease Virus Infection in Domestic Cats in Japan. J Vet Med Sci 76: 1157-1160.

Wensman JJ, Jaderlund KH, Gustavsson MH, Hansson-Hamlin H, Karlstam E, Lilliehook I, et al (2012). Markers of Borna disease virus infection in cats with staggering disease. J Feline Med Surg 14: 573-582.

Wensman JJ, Jaderlund KH, Holst BS, Berg M (2014). Borna disease virus infection in cats. Vet J 201: 142-149.

Zaliunaite V, Steibliene V, Bode L, Podlipskyte A, Bunevicius R, Ludwig H (2016). Primary psychosis and Borna disease virus infection in Lithuania: a case control study. BMC psychiatry 16:369.

 

 

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