Borna virus infection
updated September 22, 2015
The Borna virus infection guidelines were first published in the Journal of Feline Medicine and Surgery (2015) 17, 614-616; the present update has been authorised by Marian C. Horzinek.
Historically, Borna disease virus (BDV) has been known to affect 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).
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.
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 (Fig. 1) 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). Shrews could also serve as reservoirs for BDV infection in cats. Obviously, BDV infection is not readily transmitted between cats. 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 where it leads to lymphocytic inflammation and neuronal degeneration.
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.8 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).
Pathogenesis and clinical signs
Infection has been reported to start in olfactory nerve cells from where the virus spreads to the central nervous system (CNS; Wensman et al., 2014). 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 a range of clinical signs (Fig. 2), amongst others gait disturbances, ataxia, pain in the lower back and behavioural changes (Fig. 3). 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.
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 on the basis of clinical signs alone is not possible as there are several other viral infections that can lead to similar clinical signs (FIV, FeLV and FCoV). 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.
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 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.
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 chemical parameters are observed. The most important histopathological findings include perivascular cuffing (Fig. 4) 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.
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.
Bode L, Ferszt R, Czech G. Borna disease virus infection and affective disorders in man. Arch Virol Suppl 1993; 7: 159-167.
Bode L, Ludwig H. 2003. Borna disease virus infection, a human mental-health risk. Clin Microbiol Rev 2003; 16: 534-545.
Cubitt B, de la Torre JC. Borna disease virus (BDV), a nonsegmented RNA virus, replicates in the nuclei of infected cells where infectious BDV ribonucleoproteins are present. J Virol 1994; 68: 1371-1381.
Cubitt B, Oldstone C, de la Torre JC. Sequence and genome organization of Borna disease virus. J Virol 1994; 68: 1382-1396.
Hilbe M, Herrsche R, Kolodziejek J, Nowotny N, Zlinszky K, Ehrensperger F. Shrews as reservoir hosts of borna disease virus. Emerg Infect Dis 2006; 12: 675-677.
Johansson M, Berg M, Berg AL. Humoral immune response against Borna disease virus (BDV) in experimentally and naturally infected cats. Vet Immunol Immunopathol 2002; 90: 23-33.
Lin CC, Wu YJ, Heimrich B, Schwemmle M. Absence of a robust innate immune response in rat neurons facilitates persistent infection of Borna disease virus in neuronal tissue. Cell Mol Life Sci 2013; 70: 4399-4410.
Ludwig H, Bode L. Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology. Rev Sci Tech 2000; 19: 259-288.
Lundgren AL, Johannisson A, Zimmermann W, Bode L, Rozell B, Muluneh A, et al. Neurological disease and encephalitis in cats experimentally infected with Borna disease virus. Acta Neuropathol 1997; 93: 391-401.
Lundgren AL, Ludwig H. Clinically diseased cats with non-suppurative meningoencephalomyelitis have Borna disease virus-specific antibodies. Acta Vet Scand 1993; 34: 101-103.
Lundgren AL, Zimmermann W, Bode L, Czech G, Gosztonyi G, Lindberg R, et al. Staggering disease in cats: isolation and characterization of the feline Borna disease virus. J Gen Virol 1995; 76: 2215-2222.
Lundgren AL. Feline non-suppurative meningoencephalomyelitis. A clinical and pathological study. J Comp Pathol 1992; 107: 411-425.
Reeves NA, Helps CR, Gunn-Moore DA, Blundell C, Finnemore PL, Pearson GR, et al. Natural Borna disease virus infection in cats in the United Kingdom. Vet Rec 1998; 143: 523-526.
Someya A, Fukushima R, Yoshida M, Tanahashi Y, Prapeuk T, Iizuka R, et al. A Study on Borna Disease Virus Infection in Domestic Cats in Japan. J Vet Med Sci 2014; 76: 1157-1160.
Wensman JJ, Jaderlund KH, Gustavsson MH, Hansson-Hamlin H, Karlstam E, Lilliehook I, et al. Markers of Borna disease virus infection in cats with staggering disease. J Feline Med Surg 2012; 14: 573-582.
Wensman JJ, Jaderlund KH, Holst BS, Berg M. Borna disease virus infection in cats. Vet J 2014; 201: 142-149.