Rabies, lyssaviruses and bats

 SMJ 2003 48(4): 99-101

Derrick J. Pounder

Professor of Forensic Medicine

Department of Forensic Medicine

Fleming building

University of Dundee

Dundee DD1 4HN

d.j.pounder@dundee.ac.uk

The death from rabies of a bat conservationist in Dundee in November 2002 was well publicised in the media.  The case was noteworthy not only because it was the first fatal infection acquired in the UK since 1902.  The causative virus was the European bat lyssavirus type 2 (EBL 2), a strain closely related to but distinct from the classical rabies virus (1).  As the name of the virus implies, the natural reservoir of EBL 2 is in bats and not the terrestrial mammals which typically harbour classical rabies virus.  

Rabies is an acute, progressive, incurable viral encephalomyelitis first described in Mesopotamian civilisations about 4000 years ago.  The causative agent is a negative-stranded RNA virus in the family rhabdoviridae (“rod-shaped”), and genus lyssavirus (“frenzy”).  Infection usually occurs from a bite or, less often, through the contact of an open wound or mucus membrane with the saliva of an infected animal.  The incubation period is typically 20-90 days, although periods ranging from a few days to more than a year have been documented.  The virus replicates in local muscle fibres, binds to nicotinic acetylcholine receptors in the neuromuscular junction, travels by fast axonal transport (50 to 100 mm/d) to the central nervous system, replicates in the neurones of the spinal cord and dorsal root ganglia, infects brain neurones and then spreads centrifugally along nerves to the major exit portals, the salivary glands (2).  

The etiological agent of rabies encephalitis was believed to be unique until 1956, when the first rabies-related viruses were isolated in Africa and Europe.  Continuing developments in molecular biology allowed the identification of the lyssavirus genus and the delineation of seven genotypes, six of which have caused rabies encephalomyelitis in humans and/or animal deaths in nature (3).  

The seven genotypes comprise rabies virus (genotype 1), two European bat lyssaviruses (EBL type 1, genotype 5, and EBL type 2, genotype 6), Australian bat lyssavirus (ABL, genotype 7) and three other viruses isolated in subequatorial and southern African countries.   Lagos bat virus (genotype 2) has not been reported as causing human or animal deaths and has been isolated mostly from large fruit eating bats.  Mokola (genotype 3) and Duvenhage (genotype 4) viruses have been isolated mostly from small mammals and small insectivorous bats respectively.  Molecular diagnostic tools, such as nucleotide analysis, allow not only identification of genotypes but of variants within the genotypes, which can be linked with sources of the virus in specific animal reservoirs.  Molecular characterisation of rabies virus has been used to trace spillover transmission from reservoir species to non-reservoir  animals and humans, a form of “molecular epidemiology”, and also to monitor the emergence of specific strains of the virus into new species and geographic areas, that is “molecular surveillance” (4). 

Classical rabies virus (genotype 1) has a world-wide distribution and causes an estimated 35,000 to 50,000 deaths annually (5).  Globally, rabies infection ranks about 11^th in terms of mortality from infectious diseases.  Most fatalities occur in India, South East Asia and Africa, where the main animal reservoir is dogs.  In developed countries, due to effective domestic animal vaccination programmes, wild animals are the most important vectors.  In Europe the main reservoir is in the red fox and the raccoon dog, which was introduced into western Russia for fur farming in the 1920’s but subsequently spread throughout most of Eastern Europe and into Finland (6).  Transmission is typically from wild animals to dogs or cats and thence to humans.  In the UK, rabies was eliminated from the animal reservoir in the 1920’s and the 20 or so deaths reported since then have been acquired overseas (7).  A European programme of oral vaccination of foxes has significantly reduced the risk in continental Europe so that Western Europe is now effectively rabies free.  In North America the major reservoirs are in raccoons, skunks and bats (8).  In Latin America also the reservoirs are in carnivores, including dogs, and in bats (9).  Bovine rabies transmitted by haematophagous (vampire) bats continues to be a serious problem in the cattle industry in South and Central America (10), and vampire bat bites continue to be a cause of human rabies infection in rural areas (11).

Vaccination and animal control programmes in North America have produced a dramatic fall in the incidences of rabies.  Between 1980 and 1996 there were only 32 laboratory-confirmed cases of human rabies diagnosed in the US (12).  Of the 32, 12 were virus variants found in domestic dogs outside the US and half of these were associated with a definite history of dog bite in a foreign country.  However, 17 of the 32 deaths were associated with rabies virus variants found in bats, which has served to focus American attention on bats as a reservoir for classical rabies virus (genotype 1).  Surprisingly the virus variants are linked with two relatively reclusive species, the sliver-haired bat and the eastern pipistrelle, both insectivorous bats (13).  In Colorado rabies was diagnosed in 15% of 4,470 bats tested over a 20 year period (14).  Canada and Chile had similar experiences.  In 2000, Canada experienced its first rabies-related death in 15 years from a genotype 1 bat-related virus variant (15).  In 1996 Chile experienced its first human rabies case in 14 years from a genotype 1 virus variant with its reservoir in an insectivorous bat (16). 

Most cases of human rabies caused by bat variants of rabies virus (genotype 1) have no definite history of animal bite.  In these cases the method of transmission of rabies from bats to humans is unclear and the subject of considerable debate (17).  The currently favoured hypothesis is that bat bites have passed unrecognised by patients.  Alternative hypotheses include aerosol transmission, or transmission via an intermediate host.  There is little evidence of an intermediate host.  Rabies viruses from 78 dogs and 230 cats in the US in 1999 disclosed only 1 bat-associated variant, in a cat from Maryland (18).  The public health problem of deaths from cryptic exposure to bat-associated rabies virus has resulted in recommendations (19, 20) in both the USA and Canada that post-exposure prophylaxis should be undertaken even in the absence of a demonstrable bat bite, scratch or mucus membrane exposure in situations in which there is a reasonable probability that such contact occurred e.g. a sleeping person awakening to find a bat in the room. 

Australian bat lyssavirus was first isolated in 1996 and is phylogenetically closely related to genotype 1 virus (21).  Australian bat lyssavirus is currently known to infect naturally all four megachiroptera (fruit bats/flying foxes) in Australia, at least three species of microchiroptera (insectivorous bats), and humans (22).  Between them, the four Australian fruit bats have habitats extending over two thirds of Australia; the largest have a wing span of up to 1.6 metres and congregate in trees, sometimes in colonies of up to 100,000 animals.  An ongoing surveillance programme suggests that ABL is widely distributed amongst bats in Australia, and the possibility that the virus exists amongst bats of Papua New Guinea and the Philippines is currently being researched.  For public health purposes, it is assumed that all Australian bats have a potential to carry and transmit the virus.  None of the other lyssaviruses, including classic rabies virus, are found in Australia.  Two people have died from rabies-like encephalomyelitis due to ABL, the first in 1996 and the second in 1998.  In the first case (23) infection was by a strain of ABL associated with insectivorous bats, and in the second case (24) by a strain associated with fruit bats (flying-foxes).  In Australia, pre-exposure prophylaxis is recommended for people at risk of bites or scratches from bats e.g. bat handlers, veterinarians, wild life officers and others who are liable to come into direct contact with bats.  Post-exposure prophylaxis is recommended after a bite, scratch or significant salivary exposure from an Australian bat.

European bat lyssavirus infects insectivorous bats in Europe.  In continental Europe some 600 cases of rabies in bats have been reported since 1977.  On two occasions, sheep infected with the virus have been found and on one occasion the virus was found in a stone marten.  Three human fatalities were reported prior to the Dundee case: two in the former Soviet Union and one in Finland (27).  Serotine bats (Eptesicus serotinus) are the principal reservoir for genotype 5 (EBL 1) and pond bats (Myotis dasycneme) and Daubenton’s bat (Myotis daubentonii) for genotype 6 (EBL 2).  Serotine bats are relatively uncommon in Britain and the pond bat is not found.  In 1985, a notable increase in the number of recorded cases of rabies in European bats was observed, and there was concern that the disease could be introduced into the UK by bats crossing from mainland Europe.  The UK Central Veterinary Laboratory initiated a programme of screening dead bats for lyssavirus and from 1986 to 1995, 1,822 bats belonging to 23 species were screened.  These included 41 serotine bats, the species most commonly infected in Europe.  All of these bats were found to be EBL negative (25).  Subsequently EBL 2 was isolated from two bats, the first in East Sussex in 1996 and the second in Lancashire in 2002 (26).  This suggests that EBL may be endemic in the UK, as in mainland Europe, but at a low level.  Both infected bats found in the UK were Daubenton’s bat.  This species, one of 16 resident in Britain, rarely roosts in houses and rarely comes into contact with people.  The two bat species most commonly found roosting in British houses, pipistrelles and long-eared bats, have not been found so far to harbour EBL.  All bats in the UK are protected species, under the Wildlife and Countryside Act 1981, and it is unlawful to harm them or their roosts.  Current advice is that bats should not be handled, particularly if sick or injured.  Pre-exposure immunisation against rabies is recommended for licensed bat handlers and voluntary bat wardens.  There is no clear written advice on post-exposure prophylaxis in the UK, but it would be advisable for anyone who is bitten, scratched, or comes into some other type of close contact with bats.

Bat-associated variants of genotype 1 virus in the Americas seem to be maintained within bat species and rarely spill over to infect humans or other terrestrial mammals.  The same appears true of European bat lyssaviruses and the Australian bat lyssavirus.  It is possible that spill-overs of lyssaviruses from bats to other animals may have occurred repeatedly in history but have rarely been maintained.  Phylogenetic investigation of lyssaviruses suggests that classical rabies virus probably originated in the area of Europe/ the Middle East/ North Africa as the result of successful host switching from bats to carnivores, with subsequent world-wide spread facilitated by human activity through dog importation (28).  It is speculated that lyssaviruses may have originated from an insect rhabdovirus which insectivorous bats contracted from insects some 7,000 to 12,000 years ago.  Although classical rabies is probably the result of successful host switching from bats there is no evidence of such host adaptation by European bat lyssavirus.  Nevertheless, continuing molecular epidemiological and surveillance studies are a necessary precaution.  RNA viruses, such as the lyssaviruses, having a polymerase devoid of a proof-reading mechanism are the fastest-evolving organisms (29).  They produce a diverse viral population, i.e. quasi-species, ready to explore new conditions or escape defence mechanisms.  This property makes RNA viruses among the most dangerous pathogens.  Indeed, RNA viruses cause two of the six leading infectious killers, namely AIDS and measles, and are implicated in two others, acute respiratory infections and diarrhoeal diseases.  Of the 42 emerging or re-emerging infectious diseases between 1996 and 2000, 23 (55%) were caused by RNA viruses, illustrating the extent to which such viruses can threaten public heath (28). 

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