Managing emerging diseases borne by fruit bats (flying foxes), with particular reference to henipaviruses and Australian bat lyssavirus

Summary, 59S Introduction, 59S Emergence of three new viruses in Australia, 60S Hendra virus, 60S Australian Bat Lyssavirus (ABLV), 61S Menangle virus, 61S The emergence of similar viruses in Southeast Asia, 62S Nipah virus, 62S Tioman virus, 63S Australian bat lyssavirus, 63S Comments on the possible emergence of other related viruses, 63S Other viruses associated with fruit bats, 63S Management strategies, 63S Current strategies, 64S Hendra and Nipah viruses, 64S Menangle virus, 64S Australian bat lyssavirus, 64S Future strategies, 65S Can a vaccination strategy be developed to control emerging viral diseases in flying foxes? 65S Acknowledgements, 66S References, 66S Since 1994, a number of novel viruses have been described from bats in Australia and Malaysia, particularly from fruit bats belonging to the genus Pteropus (flying foxes), and it is probable that related viruses will be found in other countries across the geographical range of other members of the genus. These viruses include Hendra and Nipah viruses, members of a new genus, Henipaviruses, within the family Paramyxoviridae; Menangle and Tioman viruses, new members of the Rubulavirus genus within the Paramyxoviridae; and Australian bat lyssavirus (ABLV), a member of the Lyssavirus genus in the family Rhabdoviridae. All but Tioman virus are known to be associated with human and/or livestock diseases. The isolation, disease associations and biological properties of the viruses are described, and are used as the basis for developing management strategies for disease prevention or control. These strategies are directed largely at disease minimization through good farm management practices, reducing the potential for exposure to flying foxes, and better disease recognition and diagnosis, and for ABLV specifically, the use of rabies vaccine for pre‐ and post‐exposure prophylaxis. Finally, an intriguing and long‐term strategy is that of wildlife immunization through plant‐derived vaccination. The role of bats in the maintenance and spread of various viral diseases is well established (Sulkin and Allen 1974; Ghatak et al. 2000; McColl et al. 2000), including members of the alphaviruses, flaviviruses, rhabdoviruses and arenaviruses. However, much of the information has been gathered from members of the suborder Microchiroptera (insectivorous and vampire bats), and relatively little information is available for the members of the suborder Megachiroptera (fruit bats and flying foxes). Lyssaviruses, particularly rabies, have been identified in six genera of fruit bats (McColl et al. 2000; Van der Poel et al. 2000), but most other reports have been concerned with various flaviviruses, including West Nile (Paul et al. 1970) and Kyasanur Forest (Pavri and Singh 1968), and with two unidentified paramyxoviruses (Pavri et al. 1971; Henderson et al. 1995). Of the two paramyxoviruses, one was isolated from a Rousette fruit bat (Rousettus leschenaulti) in India (Pavri et al. 1971) and was later identified as a new animal subtype of parainfluenza virus (PIV) type 2, and the other, Mapuera virus, a member of the genus Rubulavirus, was isolated from a Yellow‐shouldered bat (Sturnira lilium) captured in the tropical rain forest of Brazil in 1979 (Henderson et al. 1995). Experimentally, fruit bats have been shown to be susceptible to infection with Japanese encephalitis (Banerjee et al. 1979, 1984) and Ebola (Swanepoel et al. 1996) viruses, the former inducing a sufficient viraemia for onward transmission by mosquitoes (Banerjee et al. 1984) and the latter also producing a viraemia with a high virus titre. However, considerable interest has recently been engendered by the emergence of novel viruses from fruit bats in Australia and Southeast Asia. This paper describes these viruses and the problems in their management. Between 1994 and 1997, three novel zoonotic viruses were discovered in Australia associated with fruit bats of the genus Pteropus (flying foxes); Hendra virus in 1994, ABLV in 1996, and Menangle virus in 1997. Their emergence was unprecedented; no similar multi‐emergence of three novel viruses belonging to two virus families and three genera, and all isolated from a single host genus, had been reported previously over such a short time frame. The first of the three viruses to appear was Hendra virus, previously called equine morbillivirus. A number of recent reviews have described the isolation, ecology, epidemiology, molecular biology, virion structure and laboratory diagnosis of Hendra virus (Daniels et al. 2001, Field et al. 2001a,b; Hyatt et al. 2001; Mackenzie and Field 2001; Wang et al. 2001). Thus the discovery and biological characteristics are described briefly here. The initial outbreak of an acute respiratory syndrome in 21 thoroughbred horses occurred in 1994, of which 14 died (Murray et al. 1995a). The other seven horses had a subclinical infection and were later killed. In addition, two humans were also infected, one of whom died (Selvey et al. 1995). The clinical features of the affected horses were consistent with an interstitial pneumonia. The detailed clinical features, together with autopsy and histological findings, have been reported elsewhere (Murray et al. 1995a, 1995b; and reviewed by Mackenzie and Field 2001). A similar picture of interstitial pneumonia was seen in the fatal human case, and at autopsy, findings were consistent with viral infection. A previously undescribed virus of the family Paramyxoviridae was isolated from lung tissues taken from the horses, and subsequently from kidney tissue from the fatal human case. The virus was named equine morbillivirus on the basis of a weak one‐way cross‐reaction with rinderpest virus, but was subsequently renamed Hendra virus (after the Brisbane suburb where the outbreak occurred). A second small outbreak in Mackay, about 1000 km north of Brisbane, came to light about 12 months later, although it actually pre‐dated the Hendra outbreak by over a month. Two horses died of unknown cause and the farmer, who had assisted at necropsy, had a mild meningitic illness, but recovered. Thirteen months later, however, the farmer became ill and died of a severe encephalitis which was shown to be caused by Hendra virus (O'Sullivan et al. 1997). Subsequent investigations demonstrated that the horses had died of Hendra virus infection (Hooper et al. 1996; Rogers et al. 1996), and the farmer had been infected at that time, but the virus had presumably remained latent and reactivated 13 months later (O'Sullivan et al. 1997). A third incident of equine infection with Hendra virus occurred in January 1999 (Field et al. 2000; Hooper et al. 2000), but only affecting a single animal. An extensive seroepidemiological investigation of wild and domestic animals was initiated to find the source of the virus (Rogers et al. 1996; Ward et al. 1996; Young et al. 1996). The only seropositive animals to be found were flying foxes (Young et al. 1996, 1997). Indeed antibodies to Hendra virus were detected in all four species of flying foxes found in Australia. These are the spectacled flying fox (Pteropus conspicillatus), which occurs in northern and eastern parts of Queensland; the black flying fox (P. alecto), which has a wide distribution across northern Australia, the little red flying fox (P. scapulatus), which is found across northern and eastern Australia, and the grey‐headed flying fox (P. poliocephalus), which occurs in eastern and south‐eastern Australia (Field et al. 2001a,b). Approximately 47% of flying foxes sampled over their full geographical range have been found to have antibodies to Hendra virus (Field et al. 2001b), although differences in seropositivity have been observed between different species (Field et al. 2001a). Three virus isolates were obtained from uterine fluid and a pool of foetal lung and liver from one grey‐headed flying fox and from foetal lung of a black flying fox (Halpin et al. 2000). These isolates were indistinguishable from the isolates of horses and the human isolate. Hendra virus is the first isolate in a new genus within the subfamily Paramyxovirinae of the family Paramyxoviridae. It differs significantly from members of the other genera within the subfamily in a number of molecular and biological properties. The complete genome of Hendra virus has been sequenced (Gould 1996; Wang et al. 1998; Yu et al. 1998a,b; Halpin 2000; Wang et al. 2000); the gene arrangement is very similar to the Respirovirus and Morbillivirus genera, but the genome size (18.2 kb) is much larger, due in part to a larger P gene and in part to longer untranslated regions at the 3′ ends of the six transcription units. The biological properties include a much wider in vitro host range, a relatively diverse in vivo host range, and a predilection for endothelial cells. The virus has an unusual double fringe comprising 15 and 8‐nm projections (Hyatt and Selleck 1996; Hyatt et al. 2001) not found in other members of the Paramyxoviridae family. There appears to be an epidemiological link with pregnancy that has yet to be fully understood, with pregnant horses as the index case in the three outbreaks, the temporal association of the outbreaks with the birthing period of species of flying foxes, and the first bat isolates being from foetal tissues (Halpin et al. 2000; Field et al. 2001a). Indeed the virus has been shown experimentally to cross the placenta in bats and guinea‐pigs (Williamson et al. 2000). With respect to public health issues and management, it is interesting to note that the three human infections have arisen from contact with infected horses and not from flying foxes. Indeed, no evidence of prior infection was found among bat carers, most of whom have a close relationship with many flying foxes each year and therefore ample for exposure (Selvey et al. 1996), among who had of exposure to infected horses as with and humans et al. In addition, no of Hendra virus infection were detected in tissue and Thus these that the virus is not particularly and transmission to humans is a very The and of transmission from bats to horses is not however, infections in a range of and investigations of infections in flying foxes and in horses, have possible of transmission and Field 2001; Field et al. has been isolated from the and of horses, and the kidney and of experimentally infected with Hendra have been infected experimentally by the and transmission and transmission have been reported et al. 1996; et al. These latter are to have most from exposure to infected spread has not been demonstrated virus in and but transmission between horses has not been observed although it occurred in the the second incident at has not yet been demonstrated in the of flying foxes. The of respiratory spread of Hendra virus be due to the in endothelial in and (Hyatt et al. 2001). Australia has been of rabies and the from the genus were known to virus, but from the genus Lyssavirus had been the of virus, had the of an virus in Australian bats in that the of the viruses in bats that an ABLV not of bats was or or a domestic animal was infected by a the for Hendra virus in bats was the for the discovery of Thus ABLV was first in a (P. from northern which was et al. 1996). It has been found to in all four species of flying fox flying grey‐headed flying little red flying and spectacled flying their Australian range, and in species of bat including the bat (Hooper et al. 1997). The of ABLV detected by in or bats in was et al. 2000). The virus was found to be similar to rabies virus and therefore a member of lyssavirus but was on and was therefore to a new (Gould et al. from the for and have that rabies vaccine a to ABLV Hooper et al. 1997). The ABLV has been for two fatal infections in bat The first occurred in a animal who had been and by a bat et al. 1996), and the second occurred in a who had been by a flying fox previously et al. 2000). In the clinical were consistent with rabies infection and a Menangle virus in as the of a severe disease that occurred in a in a and with and et al. 1998; et al. 2001). The virus was isolated from and tissues of infected and shown to be similar to viruses in the family Paramyxoviridae. of the virus has shown it to be a new member of the genus Rubulavirus, although the with other members of the genus et al. 2001). Two farm are to have been infected by the virus, with an by et al. but the of transmission from to farm is not A of grey‐headed and little red flying foxes within of the affected antibodies to Menangle virus were found in of from these In addition, antibodies were found in flying fox in to the outbreak in and from flying foxes in north km from the It is therefore that flying foxes are a host of Menangle virus, and were the source of the outbreak infection in The of spread from bats to has not been have that the virus spread between the farm and two associated by the of of the from for a period in the of the virus from the et al. 2001). In an flying foxes are to from and Australian species the of their the discovery of three novel viruses from flying foxes in Australia that similar viruses in flying fox species There are about species of bats in the genus Their distribution from the of and the of and through Asia, as as the and Australia. are not found on or and It is that the of only three species of flying foxes are to a link between the of Australia and on bats belonging to two species and from on the north of Young and and four species and from and Halpin and were found to have antibodies to a virus Field et al. 2001a). A year these were a new virus, Nipah virus, was isolated from and humans in The in the bats are consistent with Hendra virus infection. A outbreak of disease in and humans occurred in between and 1999 in human of which were and the of about et al. 2000). The disease in was and by acute with respiratory with or in all The clinical syndrome in humans was with clinical including and to within et al. et al. 2000). A virus, subsequently named Nipah virus, was isolated in et al. investigations the virus has been for disease in in The of human were or associated with was to be by the respiratory on the of Nipah virus has shown and molecular to the Hendra virus et al. 2000; et al. 2000; et al. 2001; Hyatt et al. 2001; Wang et al. although are also differences in and (Hyatt et al. 2001). This latter is for of Hendra virus in equine in and Nipah virus in respiratory Thus Nipah virus is by the respiratory between and from to However, although Nipah virus has been shown to in respiratory and of human is no epidemiological evidence of transmission from human to human et al. 2001a). The that although the two viruses are and members of a new genus, within the family Paramyxoviridae et al. also in a number of features, one of which is of wildlife species for evidence of the of Nipah virus was an part of the outbreak and of the between Nipah virus and Hendra virus wildlife on of various bat species found 21 bats from species species of fruit including the flying fox species Pteropus and with antibodies to Nipah virus (Field et al. Nipah virus was isolated from the of an flying and from a fruit et al. the for the host of Nipah virus, previously unknown virus was isolated from the of flying foxes (P. on Tioman This new virus, which is related to Menangle virus, was named the Tioman et al. related to Menangle virus, and a member of the Rubulavirus genus, Tioman virus has not yet been associated with disease in humans or However, it is a of the that other as yet viruses in across the geographical range of Pteropus Indeed other viruses have been isolated from bats in Australia and and and two of related paramyxoviruses have been described in flying foxes in Australia and Malaysia, with to one in ABLV has not been detected in or bat to This is a of and evidence of of infection in these bat However, evidence of a virus related to ABLV has been reported recently from six different bat species in the et al. four of which were species in the Microchiroptera and and two in the Megachiroptera (Pteropus and The that other related viruses be to the range of Pteropus and in other genera of fruit bats the or similar The various differences is and observed between Hendra and Nipah viruses not be as probable of the properties of other related the host be or humans be and related viruses different of and be between The only to be that related viruses and will or be from their in their geographical range on members of the genus In Australia, viruses use flying foxes as a The viruses of interest are the and and the Japanese The evidence for an of flying foxes in the of virus was on found in flying foxes in the of et al. transmission of virus was demonstrated between grey‐headed flying foxes (P. and mosquitoes et al. 1997). et al. found a much of mosquitoes a flying fox in well from the is evidence that flying foxes a role in the of There is as yet no evidence that flying foxes are in the of Forest virus, but as the two various and it be a Japanese encephalitis virus has been shown to be to and from two species of fruit bat in (Banerjee et al. and (Banerjee et al. and with the spread of Japanese encephalitis virus to the of northern Australia et al. is that flying foxes in an The management of a novel or viral disease is most a and The issues include a of the disease of transmission and and for laboratory and an of the public health and animal health and the potential and The will be directed first at management and practices, and at a possible of wildlife vaccination as a strategy for control. Hendra virus and a Nipah virus, of the of transmission in the from the to and from to is The transmission from to only be and a number of possible have been (Field et al. the two viruses in their between and from which is a of their (Hyatt et al. 2001). for viruses, is no evidence transmission et al. Field et al. Mackenzie and Field 2001). to Hendra virus infection in horses include and exposure to flying foxes be by horses at and by flying fox from of the of flying transmission and of for will of management to infection in It be that only horses geographical with the of flying foxes are as and have where infection has occurred in horses, assisted by the of Hendra virus in horses et al. 1996). management include a high of and by and other where horses with severe respiratory Hendra virus is be as and as well as be laboratory is also an in disease control and management. The outbreak that Nipah virus in was and the of transmission was respiratory (Daniels et al. 2000). The of transmission between was the of a number of strategies be to the potential for an outbreak of Nipah virus infection. The strategy is the of farm management such as health and recognition of disease In addition, the of the of new be (Daniels et al. 2000). management to from flying foxes to are also possible in with a little with is a and The of fox contact be by the of flying fox in the of It is also that a laboratory is available with to where to and outbreak of Menangle virus management are similar to for Hendra and Nipah Thus it is to to contact through fruit and from and and that are not close to flying fox Management within the to Menangle virus infection has been through of et al. 2001). Australian bat lyssavirus management differs significantly from the other novel bat transmission has been between bats and in fatal infections similar to a vaccine is available which from infection with and the virus has been found in flying foxes and bat the other viruses, are no with human infection to exposure to infected management of the public health has public to This strategy is by vaccination. The from vaccine that rabies vaccine infection with ABLV Hooper et al. had public health However, a has been the public that bats are and a to of and 2000). vaccination with rabies vaccine is for high such as wildlife and of vaccine and rabies is to to bats through or ABLV infection be in the In a of in potential exposure in animal for of potential their family members for animal for members who bats for and members with initiated by bats for et al. 2000). Indeed the of has and has a public health in where ABLV had not been detected and Thus the of bat and the public about the in bats be and the for et al. 2000). The evidence that ABLV only in and case investigation and have found no evidence of ABLV infection in domestic animal species (McColl et al. or wildlife species Field However, to have that and experimentally infected with ABLV in clinical of disease McColl of and flying foxes evidence of infection with Hendra and ABLV et al. are no vaccination in to and spread of these viruses within the many and by the management of viral in wildlife is not The of disease control of the management available and an of the and the and This is well by the rabies virus of domestic and livestock vaccination rabies in the latter of the rabies in wildlife have the source of for human infection et al. 2001). This is the case for bat in the which have caused of the human rabies between and et al. 2001). different have been to the of rabies control in wildlife with of was used for management of rabies in vampire bats in However, control strategy is and as the used are or and of the animal species have in their et al. vaccination vaccination have also been used for rabies control in of human et al. although of to animal is as well as for vaccination vaccine and or virus the have been the most to infection in These are within to the species et al. 1996), the to be to of wild animals or with the vaccine which is the Since their wildlife rabies have about a in the and spread of rabies in foxes, and in of and et al. 1996; et al. 1998; and one has been to the of the vaccine for rabies control in vampire bats, and it that be in the bats vaccine et al. This that an vaccination be for It be however, that vaccination with the spread of in wildlife these have the of being and to in This a public health distribution occurs close to human as exposure to vaccine viruses through contact with or recently animals in human infection et al. 1998; et al. 2001). it is possible for to and cause be a to animal virus for control of in flying foxes. The use of to human and animal disease has much interest over the with the vaccine are are by to and of infection in species and and 2000; and 2001). other the which the of the respiratory and the at which many first have contact with the of at the host the be to a and reviewed in and such that antibodies be detected in and have shown that virus, respiratory virus, virus and and disease virus in and have been to the in et al. 1996; et al. 1998; et et al. 2000; et al. 2001; et al. 2001). the of virus were better from infection animals with a vaccine et al. 2001). use a similar vaccination for flying foxes, it to be of is to a and that is from the or the and of flying foxes investigation to of that are to flying foxes but of little interest to Indeed, it has been found that flying foxes are particularly to (P. an which in developing a It is also to note that antibodies to Nipah virus, Hendra virus and ABLV have been detected in flying foxes (Young et al. 1996; Halpin et al. 2000; Field et al. in to between and infected animals have from infection or are also to be to the of a in the vaccine an is an which flying foxes are to have had exposure to and which also an In of the and the of are as also the to the vaccine et al. 2001). Other are or from viruses other by the which are not found to or cause disease in flying foxes. It is that of flying fox to be an viral vaccine strategy be developed to emerging viral However, are in for and of vaccine to flying foxes, be to vaccination of other or wildlife species to the spread of zoonotic to McColl for to and and Rogers for their