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Bornavirus: Zoonotic and animal health aspects
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Between late 2011 and 2013, three men in succession — aged 63, 62 and 72 years — from the state of Saxony-Anhalt, Germany, suffered a progressive encephalitis or meningoencephalitis that led to death within 2 to 4 months after the onset of clinical symptoms. The clinical course was characterized by fever, shivers, or both; progressive psychomotor slowing; confusion; unsteady gait; myoclonus, ocular paresis, or both; and finally, coma. All three were breeders of variegated squirrels, a tree squirrel that is endemic in Central America from south Chiapas, Mexico, to Panama. They were friends, had met privately on a regular basis, and had exchanged their squirrel-breeding pairs on multiple occasions. At least two of the men had been scratched by their squirrels in the past; one had been bitten.
With the use of a metagenomic approach that incorporated sequencing and real-time reverse-transcriptase quantitative PCR, or RT-qPCR, the presence of a previously unknown bornavirus was detected in a contact squirrel and in brain samples from the three patients. Phylogenetic analyses showed that this virus, tentatively named “variegated squirrel 1 bornavirus” (VSBV-1), forms a lineage separate from that of the known bornavirus species.
During the first weeks of 2016, the Friedrich-Loeffler-Institut (FLI), Germany’s National Institute for Animal Health, detected further cases of VSBV-1 in pet squirrels from zoos and breeders. Variegated squirrels as well as several species of the subfamily Callosciurinae were affected. All infected squirrels were detected in Saxony-Anhalt, Saxony, Schleswig-Holstein, North Rhine-Westphalia, and Lower Saxony. Consequently, on March 1, FLI released a recommendation to test all pet squirrels for the virus, particularly prior to their sale or purchase. Newly acquired squirrels should be retested after 3 months to detect infections contracted during the time of purchase, and entire holdings after approximately 12 months.
FLI indicated that it was yet unclear if the animals were infected in Germany or if the pathogen was imported with infected animals. The transmission routes of VSBV-1 among squirrels and between squirrels and humans were unknown; “direct transmission by scratches or bites is most likely,” according to the institute. Instructions on sampling and the shipping of samples were provided.
History of Borna disease
Borna disease (BD) is one of the oldest known viral infections in domestic animals, initially known as a horse disease. Until recently, the disease has been considered limited to Central Europe, mainly in German-speaking countries, affecting primarily horses in a seasonal pattern. Most of the research and the subsequent relevant publications on BD were written, up to the mid-20th century, in the German language.
The oldest report describing typical characteristics of an equine “head disease” dates back to 1660. A book published in 1716 recorded sleepiness, melancholia and agitation in the affected horses. Similar and more precise reports followed in the 18th and 19th centuries, mostly applying the German term for “head disease.”
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In numerous observations, which became available during the 19th century from several regions in east and south Germany, various expressions, both in German and in Latin, were used, such as “Encephalitis et Myelitis enzootica equi,” “Encephalomyelitis enzootica,” “Meningitis cerebrospinalis enzootica,” “Meningitis subacuta cerebrospinalis,” “Meningoencephalomyelitis simplex enzootica equorum,” “Polioencephalomyelitis non purulenta infectiosa” and “sleepiness disease.”
From 1891 to 1895, the disease heavily affected the surroundings of the city of Borna in Western Saxony. This probably encouraged a veterinarian named Kohl, who was observing horses with fatal subacute meningitis elsewhere, to use the term “Borna’sche Krankheit” (Borna disease) in 1896. This was followed by others, and since then, the term persisted, becoming generally accepted by the scientific community since the second decade of the 20th century. Later, the name became “Borna disease,” often abbreviated as BD.
The yearly epidemic appearance of BD in the Borna region gave rise to an increasing interest in its research. Severe losses in the horse population led to the establishment of a state-governed hospital close to Borna. The pathology of the disease was elaborated; in 1909, Joest and Degen described inflammatory reactions, mainly in the midbrain, and pathognomonic intranuclear inclusion bodies in neurons of the hippocampus, coined “Joest-Degen bodies.”
Figure 1. The variegated squirrel (Sciurus variegatoides).
Source: snowmanradio/Kathy & Sam from Beaverton OR, USA.
First reports on BD in sheep are found in the papers of the Veterinary Services in the Kingdom of Saxony, dated 1896. The viral etiology of BD was established in 1924. In 1926, the infection was successfully transmitted from diseased sheep to rabbits and guinea pigs; it was concluded that the natural disease in horses and sheep was caused by an identical agent.
Results of investigations in the 1980s and 1990s indicate that Borna disease virus (BDV) infections are distributed worldwide, while classical BD in horses and sheep is mainly concentrated in parts of Germany and Switzerland.
In addition to the information on clinical disease in several mammals, other animals were infected experimentally. The host range of BDV is likely to include most warm-blooded animals. Reports of asymptomatic, naturally infected animals suggest that the virus may be circulating wider globally than previously thought. Neither the reservoir nor the mode of transmission is known. Olfactory route for transmission has been proposed because intranasal infection is efficient; the olfactory bulbs of naturally infected horses show inflammation and edema early in the course of disease. Experimental infections of rodents resulted in virus persistence, associated with the presence of viral gene products in saliva, urine and feces; such secreta/excreta are known to be involved in the transmission of other pathogenic viruses (eg, lymphocytic choriomeningitis virus and hantaviruses). Experimental infection of bank voles led to chronic infection and excretion without major pathology or symptoms. Thus, the rodent provides the potential for both a natural reservoir and vector. Indeed, natural BDV infection has now been reported in rodents.
Until the 1980s, BDV was considered an “undifferentiated” virus. In 1992, a method for the isolation of viral particles was described, allowing definitive identification of the genome as containing a negative-stranded RNA of 8.9 kb. Further, it was shown that the viral mRNAs are transcribed in the nucleus. Following the characterization of the enveloped virion and the sequencing, a new virus family — Bornaviridae — was accepted in 1996, including one single species, Borna disease virus.
All biological and molecular properties suggest that the virus is an evolutionary old pathogen, perfectly adapted to a highly specialized cell, the neuron. This survival strategy has continued to fuel interest in this agent from veterinary and medical quarters.
A wide spectrum of other warm-blooded animals has been found to undergo natural infection, including zoo animals, wild mammals and, recently, several avian species. Experimental infections involved the tree shrew, rhesus monkey, chicken, rat, mouse, hamster, Mongolian gerbil, guinea pig and bank vole. Experimental infections of tree shrews and rats served to examine the effects of persistent and overt disease, virus-induced behavioral changes, and emotional and learning deficits. Despite the wide possible host range, the incidence of clinical BD in species other than horses and sheep appears very low.
Bornavirus-related disease in avians
In 2008, a BDV-related novel virus species was found by a pan-viral microarray screening method in domesticated and wild psittacine birds suffering from a hitherto undefined syndrome, “Proventricular dilatation disease/Macaw wasting disease.” The Borna virus affecting birds has been proposed as a separate (second) member of the family Bornaviridae, “Avian bornavirus” (ABV), of the order Mononegavirales. ABV was recorded also in ostriches (Israel) and in geese and trumpeter swans (Canada). BDV RNA positivity of mallards and jackdaws has been reported. It is possible that birds host and transmit BDV in addition to the phylogenetically closely related ABVs, but this remains to be shown. So far, seven ABV genotypes have been identified altogether.
Since BDV antibodies were reported to be detected in patients of psychiatric institutions, and given that BDV is known to infect a wide variety of animal species with a predilection for the limbic system and occasionally induces persistent emotional, cognitive and behavioral alterations in experimental animals, the question has arisen of whether the virus could also be a human pathogen and cause neuropsychiatric disorders. This issue remains controversial.
In a recent paper on the squirrel-related human cases in Germany, Hoffman and colleagues proposed to classify VSBV-1 as a new bornavirus in accordance with the latest criteria proposed by the International Committee for Taxonomy of Viruses Bornaviridae Study Group, on the basis of the phylogenetic analyses and the nucleotide sequence identities of less than 75% between this squirrel-borne bornavirus and those of the most closely related classic Mammalian 1 bornavirus sequences.
Additional activities should concentrate on (inactivated) biologicals of animal origin used for medication in humans, particularly when uncontrolled (eg, in human reproduction and in transplantation medicine). These biologicals may transfer health hazards such as BDV, emphasizing the need for surveillance of this persistent infection in the sourced animals. Given the possibility that BDV could represent a zoonotic agent, greater knowledge of its transmission is urgently required.
Until recently, BDV has been regarded as a possible, but not verified, zoonosis. The tragic event affecting the three squirrel breeders from Saxony-Anhalt might become a turning point in this discussion. The further handling of the case by the animal and public health authorities in Germany and elsewhere deserves to be followed with interest.
- References:
- Friedrich-Loeffler-Institut. Variegated squirrel 1 bornavirus (VSBV-1). https://openagrar.bmel-forschung.de/servlets/MCRFileNodeServlet/Document_derivate_00014101/Steckbrief_VSBV-1_20160301_engl2.pdf. Accessed March 29, 2016.
- Hoffman B, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1415627.
- Joest E, et al. Z Infkrankh Haustiere. 1909;6:348-356.
- Kinnunen PM, et al. J Gen Virol. 2013;doi:10.1099/vir.0.046961-0.
- Kohl. Ueber die “Borna’sche Krankheit” der Pferde. Berl. Thierärztl. Wochenschr. 1896;12:462-464.
- For more information:
- Arnon Shimshony, DVM, is an associate professor at the Koret School of Veterinary Medicine of the Hebrew University of Jerusalem, Rehovot, and is the ProMED-mail animal diseases zoonoses moderator. Shimshony was chief veterinary officer, State of Israel, from 1974 to 1999. He also is a member of the Infectious Disease News Editorial Board.
Disclosure: Shimshony reports no relevant financial disclosures.