infections by viruses of the families bunyaviridae and filoviridae

Rev. sci. tech. Off. int. Epiz., 2000,19 (1), 79-91

Infections by viruses of the families Bunyaviridae and Filoviridae

H. Zeller & M. Bouloy

Unité des arbovirus et virus des fièvres hémorragiques, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15, France

Summary

Rift Valley fever is the most important bunyaviral disease of animals in Africa. The virus, transmitted by mosquitoes, causes abortions and mortality in young animals in addition to haemorrhagic fevers in humans. Although vaccines against this virus are available, the uses of these vaccines are limited because of deleterious effects or incomplete protection, justifying further studies to improve the existing vaccines or to develop others. Nairobi sheep disease is transmitted by ticks. The disease is endemic in East Africa and sporadic cases are reported in India and Sri Lanka. Other viruses transmitted by mosquitoes or midges are teratogenic in cattle or sheep, these include Akabane and related viruses in Asia, Australia and the Middle East, and Cache Valley in North America. The Marburg and Ebola viruses of the genus Filovirus are associated with epidemics in Central Africa with high fatality rates in humans; some outbreaks were related to contact with monkeys. Another subtype of Ebola virus was first described in a quarantine facility in the United States of America among cynomolgus monkeys (Macaca fascicularis) from the Philippines. The reservoir of these viruses remains unknown.

Keywords

Animal diseases - Bunyaviruses - Ebola virus - Filoviruses - Marburg virus - Monkeys -Nairoviruses - Phleboviruses - Public health - Rift Valley fever - Zoonoses.

Introduction The Bunyaviridae family compr ises m o r e than 300 m e m b e r s

grouped into five genera n a m e d Bunyavirus, Hantavirus,

Nairovirus, Phlebovirus and Jospovirus, the latter is c o m p o s e d

of viruses infecting plants only (32) . Wi th the excep t ion of

hantaviruses, a genus of viruses w h i c h is transmitted b y

rodents and w h i c h is descr ibed in a separate paper in this

volume (14), m e m b e r s of the family Bunyaviridae are

transmitted b y ar thropods, m o r e specifically b y mosqui toes ,

ticks, ph lebo tomines and biting midges (24) (Table I).

Although mos t of these viruses infect a variety of vertebrate

hosts, including laboratory animals (mice, hamsters and rats),

which are widely used for virus isolation, only a f ew are

responsible for zoonoses . T h e mos t important of these is Rift

Valley fever (RVF) virus w h i c h is transmitted b y mosqu i toes

to livestock in Africa. Most of the other viruses have a

c o m m o n t ropism for foetal tissues and cause embryonic

and foetal death, stillbirths and multiple congenital

malformations. These viruses be long to different genera and

serogroups and are widely distributed. Among m e m b e r s of

the genus Bunyavirus, Akabane from the Simbu serogroup is

found in Australia, Asia and the Middle East, and Cache

Valley from the Bunyamwera virus serogroup is present in

North America. Among m e m b e r s of the genus Nairovirus,

Nairobi s h e e p disease circulates in East Africa and India. In

addit ion to these viruses, Crimean-Congo haemorrhagic fever

virus was reported to infect domest ic animals w h i c h b e c a m e a

source of contamination for humans (52) . This virus is widely

distributed throughout Africa, the Middle East, southern

Europe and Asia, and is transmitted by t icks to l ivestock and

birds such as ostriches. T h e infection is asymptomatic in

animals but the virus is highly pathogenic in humans ,

resulting in haemorrhagic fevers with possible nosocomia l

infections. T h e main sources of h u m a n contamination are

infected tick bites or infectious aerosols p r o d u c e d b y viraemic

animals in slaughterhouses (49, 52) .

Rift Valley fever and Crimean-Congo haemorrhagic fever

viruses are highly pathogenic, causing lethal haemorrhagic

fevers in humans , thus generating serious publ ic heal th

p rob lems . Viruses belonging to other families are responsible

80 Rev. sci. tech. Off. int Epiz., 19 (1)

Table I Geographic distribution, vectors and hosts of Bunyaviridae of animal importance and related human disease

Genus Virus Geographic distribution Vectors Hosts Animal disease Human disease

Phlebovirus Rift Valley fever Africa Mosquitoes Ruminants Abortions, new-born mortality, hepatitis

Haemorrhagic fever

Nairovirus Nairobi sheep disease East Afr ica, India, Sri Lanka Ticks Sheep, goats Haemorrhagic gastroenteritis None

Crimean-Congo haemorrhagic fever

Africa, Middle East, Asia, southern Europe

Ticks Ruminants, birds, rodents, hares

None Haemorrhagic fever

Bunyavirus Akabane Australia, Japan, Taipei China, Republic of Korea, Middle East, Kenya

Mosquitoes, bit ing midges

Livestock - Congenital malformation None

Aino, Tinaroo, Douglas Australia, Japan Biting midges Livestock Congenital malformation None

Cache Valley North America Mosquitoes Sheep Congenital malformation Not documented

Main Drain North America Mosquitoes, biting midges

Equines, rodents

Encephalomyelitis, congenital malformation in sheep (experimental)

Not documented

La Crosse North America Mosquitoes Rodents Congenital malformation in sheep (experimental)

Encephalitis

San Angelo North America Mosquitoes Host unknown Congenital malformation in sheep (experimental)

Not documented

for similar haemorrhagic manifestations, for example , yel low fever and dengue viruses in the family Flaviviridae, Lassa and South American haemorrhagic fever viruses in the family Arenaviridae, and Marburg and Ebola viruses in the family Filoviridae. In c o m m o n with hantaviruses, arenaviruses are transmitted b y rodents wh ich are chronic carriers of these viruses and represent an excellent reservoir. T h e hos t reservoir for filoviruses is still undetermined, al though filovirus-infected m o n k e y s have b e e n documented . Zoonoses associated with these viruses will b e presented in the last section of this paper.

Bunyaviridae Rift Valley fever Introduction and history Rift Valley fever was first descr ibed near Naivasha in the Rift Valley of Kenya in 1931 b y Daubney et al. (9) , w h o isolated the causative viral agent wh ich was classified later as a m e m b e r of the genus Phlebovirus of the family Bunyaviridae. Major outbreaks were recorded in Kenya in 1968, 1978-1979 and 1997-1998, in addition to southern Africa, South Africa, Zimbabwe, Zambia and Madagascar (30, 36 , 47 ) . T h e RVF virus was isolated for the first time in 1974, in Wes t Africa, from Aedes mosqui toes . Later, the virus was also detected in Mauritania, Mali and Guinea. Circulation b e y o n d the sub-Saharan countries was not reported before 1977, w h e n a sudden and dramatic outbreak occurred in Egypt; the virus reappeared in the same region in 1993. Manifestations of the virus were observed in Madagascar in 1990-1991 , in Kenya, Tanzania and Somalia in 1997-1998 , and in Mauritania in 1998. A recent study indicated that the viruses circulating in Madagascar in 1990 and in Kenya in 1997 were closely related (42) .

Impor tance for an imal and public health T h e disease was first descr ibed as an enzootic hepatitis with extensive necrosis, leading to the rapid death of new-born lambs. During a notable epizootic of RVF in South Africa in 1950 and 1951 , 100,000 s h e e p d ied and 500 ,000 aborted. Before the ep idemic in Egypt in 1977, RVF was essentially k n o w n as a disease wh ich affected domest ic animals, especially s h e e p , cattle and goats, producing h igh mortality in new-bo rn animals and abortions in pregnant animals, with only a few fatal h u m a n cases reported. However , since 1977, outbreaks have not only caused great e conomic losses in l ivestock, but humans have also b e e n affected b y the disease. Infections in humans occur after contact with infected animals or mosqui to bites. T h e disease has a w i d e variety of clinical manifestations, generally beginning as an influenza-l ike illness wh ich is usually without sequelae , howeve r in s o m e cases, severe complicat ions, such as retinitis, encephalitis and fatal haemorrhagic fevers, are observed . In 1977, b e t w e e n 18,000 and 200 ,000 h u m a n cases were estimated to occur in Egypt, with 600 recorded deaths from encephalitis and/or haemorrhagic fevers. In 1987, 224 p e o p l e d ied from RVF virus in Mauritania. An estimation of the number of h u m a n and animal cases of RVF in 1997-1998 in East Africa was difficult due to the circulation of numerous pathogens, however , m o r e than 89 ,000 humans were infected, indicating that this was probably the mos t important ep idemic recorded (3).

Aet iological agent and classif icat ion Rift Valley fever virus was classified as a m e m b e r of the family Bunyaviridae and the genus Phlebovirus (19, 45 ) . Negative staining revealed enve loped particles, measuring 90 n m to 110 n m in diameter, wh ich are c o m p o s e d of a tripartite single-stranded ribonucleic acid (RNA) g e n o m e and four structural proteins consisting of two glycoproteins, G l and

Rev. sci. tech. Off. int. Epiz., 19(1) 81

G2, a nucleoprotein, N, and an RNA-dependent RNA polymerase , called the L (large) protein (Fig. 1). The three segments of the g e n o m e w h i c h are associated with multiple copies of the N protein and a few copies of the L protein form the inner circular and helical ribonucleoproteins. In c o m m o n with all the e n v e l o p e d viruses, RVF virus is sensitive to ionic and non-ionic detergents, hypochlor i te and c o m m o n disinfectants. T h e N protein appears as the major antigen during infection. T h e enve lope glycoproteins G l and G 2 carry epi topes w h i c h induce neutralising antibodies wh ich were s h o w n to play an important protective role against infection.

The comple t e g e n o m e of RVF virus has b e e n sequenced , indicating that the L (large) and M (medium) segments are of

a)

N : nucleoprotein Gl : glycoprotein 1 L : large protein G2 : glycoprotein 2

b)

Fig. 1 a) Schematic representation of a viral particle of Rift Valley fever (RVF) virus b) RVF virions in extracellular space of the Vero cells after five minutes adsorption Ultrathin section counterstained with uranyl acetate and lead citrate Photo: courtesy of Dr A. Topilko and Dr A. Billecocq

negative polarity and the S (small) segment utilises an ambisense strategy, expressing the N protein and the non-structural protein c o d e d b y the S segment (NSs) proteins from the antigenomic and genomic stranded RNA, respectively. As is the case for all the viruses of this family, the viral particles mature by budding through the m e m b r a n e s of the Golgi apparatus. Exceptions to this rule were repor ted in infected rat hepatocytes and in epithelial cells of the midgut of infected mosqui toes , where budd ing from the plasma m e m b r a n e was obse rved (2).

Epidemiology In addit ion to contamination by contact with infected tissues, RVF virus is generally transmitted b y mosqu i to bites. Numerous strains of RVF virus have b e e n isolated from various species of mosqu i toes , including Aedes, Culex and Mansonia, in addit ion to Culicoides, and occasionally from ticks. T h e occurrence of ep idemics or epizootics following per iods of heavy rains or in association with the building of dams , for example , in Aswan in 1977, or o n the Senegal River in 1987, appears to b e related to particularly dense populat ions of mosqui toes (Fig. 2) . Analysis of records of rainfall and vegetation index data, coup led with satellite observations demonstrated that outbreaks could b e predicted u p to five mon ths in advance in East Africa (27). During inter-epidemic per iods , the virus is maintained in nature via transovarial transmission in mosqui toes , as s h o w n in Aedes lineatopennis in Kenya and in Ae. vexans in Senegal (54) . Recently, infection of Aethomys namaquensis rodents b y RVF virus has b e e n reported; these rodents were able to propagate the virus and might b e involved in a vertebrate-mosquito cycle, thereby constituting a possible reservoir for the virus in South Africa (38).

Phylogenetic analysis of strains of various geographical origins isolated from different hosts (humans, animals and mosqui toes) wh ich was per formed during ep idemics / epizoot ics or during endemic/enzoot ic per iods , indicated the existence of three lineages, namely: Egyptian, West African and East-Central African (43). Extended analyses per formed b y sequencing regions in the three genomic segments, strongly suggested that s o m e of the strains were generated b y genomic reassortment b e t w e e n phylogenetically different viruses, indicating that RVF viruses of different origins were present at the same time and location and h a d co-infected mosqui to or vertebrate hosts.

Biology of infection In n e w - b o m lambs of less than one w e e k of age, the mortality rate is 90%. The incubation per iod may b e as short as twelve hours, but usually lasts from 24 h to 36 h , after w h i c h the animal deve lops a h igh fever, exhibits abdomina l pain and dies within 24 h to 36 h of the onset of the first clinical signs. Older animals exhibit various clinical signs, from inapparent to peracute or acute infection; the latter form is the m o s t frequent under field conditions. Sick animals exhibit fever, anorexia, nasal discharge, b l o o d y or foetid diarrhoea and, in

82 Rev. sci. tech. Off. int. Epiz., 19(1)

Enzootic Epizootic > Epidemic

Fig. 2 Rift Valley fever virus cycle involving mosquitoes, animals and direct transmission to humans

some cases, a severe icterus. For pregnant animals, abortion may occur at any stage of pregnancy. Abortion rates are usually very high, ranging from 40% to 100% in southern Africa, or 80% to 100% in Egypt in 1977. Mortality rates of 10% to 30% or higher, have been recorded in adult cattle and sheep, depending on the nutritional state of the animal.

In humans, RVF is usually benign, resulting in fever, headache and myalgia, followed by a complete recovery. However, in some cases infection progresses to severe and sometimes fatal complications, such as retinitis, encephalitis and haemorrhagic fever with acute hepatitis. The latter was observed in 1% of the cases in Egypt in 1977.

Pathogenesis The disease affects primarily the liver, with rapid hepatocellular changes progressing to massive necrosis. In some animals, haemorrhages are observed in the liver. Experimental infections of susceptible animals have helped to understand RVF pathogenesis more fully. Infections of mice, hamsters and some strains of rats, by peripheral routes with virulent strains, lead to a transient viraemia followed by an acute hepatitis and death. In other strains of rats, RVF virus infection provokes encephalitis. Some other strains are completely resistant with asymptomatic infection (1). Resistance was shown to be governed by a dominant Mendelian gene. Rhesus monkeys (Macaca mulatto.) represent an excellent model for human infection. These animals exhibit a variety of clinical symptoms, including haemorrhagic forms with disseminated intravascular coagulation.

Diagnosis and survei l lance Since epizootics or epidemics of RVF are usually preceded by heavy rains, a high density of mosquitoes and frequent abortions in sheep and cattle, these criteria should be considered as an indication of the possible circulation of the virus. Liver lesions found by histopathological examinations provide a good indication of RVF infection. When infected liver sections are observed under electron microscope, many hepatic cells appear disorganised with nuclei containing rod or fibre-like structures composed of NSs protein. During an outbreak, a clear demonstration of the presence of the RVF virus must be obtained by virological and serological methods. Isolation of the virus after inoculation of suckling mice, or in Vero cells, is considered to be the method of choice. Diagnosis can also be performed by detection of RVF virus-specific immunoglobulin M (IgM) or IgG in animal or human sera as the presence of IgM indicates a recent infection. The enzyme-linked immunosorbent assay (ELISA) is widely used in reference laboratories and preferred to the previously established methods of complement fixation, inhibition hemagglutination and plaque-reduction neutralisation. More recently, detection of the viral genome by reverse transcriptase polymerase chain reaction (RT-PCR) amplification has been developed and was found to- be very useful for rapid diagnosis. This technique could be followed by sequencing to characterise the strains further.

Prophylaxis and t r e a t m e n t On account of the economic importance of the disease in sheep and cattle, efforts have been made to produce a veterinary vaccine. The Smithburn neurotropic strain was

Rev. sci. tech. Off. int. Epiz., 19 (1) 83

obtained b y intracerebral passages of the virulent strain, Entebbe, in suckling m i c e and embryona ted eggs (46) . However, the strain was not attenuated complete ly since this live attenuated vaccine is still neurotropic and p rovokes a range of anomalies of the central nervous system in foetuses, such as porencephaly , hydrancephaly and microencephaly . Vaccination of e w e s m a y also result in abort ion and still birth. Teratogenic effects associated with vaccination have b e e n reported in u p to 15% of pregnant ewes . For this reason, other attenuated strains have b e e n p r o d u c e d or isolated. One of these, the mutagenised strain MP12, w h i c h was derived from a virulent strain isolated in Egypt in 1977, appeared to b e a g o o d candidate b e c a u s e of the presence of attenuating mutations in each of the three segments of the g e n o m e (6, 44 ) . However, a l though this virus was an efficient i m m u n o g e n in adult and young animals, deleterious effects were observed after vaccination of pregnant ewes in the first three mon ths (B. Erasmus and D.H.L. Bishop, personal communicat ion) . Recently, a naturally attenuated strain, c lone 13, wh ich was isolated f rom a benign h u m a n case, was found to b e highly immunogenic for mice . Interestingly, this RVF virus possesses a large delet ion in the gene coding for the non-structural NSs which seems to b e an important determinant for attenuation (51).

In terms of treatment, administration of antibodies, interferon, interferon inducer or ribavirin in mice , rats or monkeys w h i c h h a d b e e n experimentally infected with RVF virus, was demonst ra ted to b e efficient in protecting against the disease (35) .

Perspect ives Recent ep idemics in East and Wes t Africa have emphas i sed the importance of irrigation and rainfall in the re-emergence of the virus, in addit ion to a risk of importat ion from Africa. Since mosqu i toes play an important role in viral transmission and propagation, means for mosqu i to eradication should b e implemented. Of utmost importance is the control of the circulation of the virus during entomological or serological surveys or virus isolation f rom captured mosqu i toes or sentinel herds . To this end, m e t h o d s for rapid detect ion of the virus b y immunocapture-ELISA or RT-PCR amplification have b e e n , or are in the process of being, deve loped . Vaccination of at least the mos t susceptible animals, i.e. s h e e p , cattle and goats, wou ld also prevent or reduce circulation of the virus and contaminat ion of humans .

Akabane and related teratogenic viruses Introduction and history Akabane is the major cause of epizoot ics of congenital malformations in ruminants in J apan and Australia. T h e virus has also b e e n identified in the Republic of Korea, Taipei China and the Middle East (Israel and Oman) , and sporadic outbreaks have b e e n suspected in other countries. Biting midges and other b lood- suck ing ar thropods transmit the virus to vertebrates (41) . Akabane was first isolated from mosquitoes in J a p a n in 1959, but association of the virus with

disease was recognised during epizoot ics from 1972 to 1974 in Japan , w h e n 42 ,000 calves out of a popula t ion of 3.6 mill ion were premature, stillborn or de fo rmed . Another large ou tbreak was r eco rded in 1974 in Australia, w h e n 3,000 calves died. In the 1950s and 1960s, epizootics with similar pa thology were repor ted in J a p a n and Australia, but the aetiological agent was unknown . Other viruses related to Akabane in J a p a n or Australia are involved in teratogenic disease, namely: Aino, Tinaroo, Douglas and Peaton. Antigenic and genetic compar isons of s o m e of these viruses suggest ev idence of natural virus reassortants. Antigenic and genetic compar isons of s o m e of these viruses suggest ev idence of natural virus reassortants (4). Molecular studies have not s h o w n variations b e t w e e n strains with different virulence.

Epidemiology

Cattle, s h e e p , goats, buffalo and horses appear to b e infected b y the Akabane , Aino and other related viruses. Antibodies to Akabane virus were repor ted in pigs in Taipei China, Indonesia and the Philippines, and in horses in Thailand. Other serological surveys have demonstrated antibodies to Akabane virus in domest ic animals in Malaysia, the Republic of Korea, Japan , South Africa, Kenya, the Sudan, Cyprus, Syria and Turkey. In Kenya, a wide range of wild ruminants were found to b e carriers of Akabane antibodies (waterbuck, impala, wi ldebees t and zebra) . Pigs appear to b e infected b y Peaton virus in Australia, but not b y the other four viruses. These viruses d o not cause disease in humans .

Akabane and related viruses have b e e n isolated in healthy domest ic ruminants in several countries, but rarely from aborted foetuses or affected animals, as reported in Japan , Australia and Taipei China. The virus is eliminated f rom the mother and foetus long before the results of damage are detected. In non-pregnant animals, the infection is hardly noticeable. Although the disease also occurs naturally in sheep , the true economic impact has not yet b e e n evaluated.

Several mon ths after the per iod of viral transmission, epizootics of disease are revealed w h e n calves or lambs are close to term. Shorter gestation in s h e e p (five months) , c o m p a r e d with the gestation per iod in cattle (nine months ) , could restrict the vulnerability of sheep .

Akabane and related viruses have b e e n recovered f rom mosqui toes such as Culex tritaeniorhynchus and Ae. vexans in Japan , or Anopheles funestus in Kenya, and f rom biting midges , principally Culicoides brevitarsis, in Australia, C. oxystoma in J apan and C. imicola in South Africa and Oman. In Australia, the presence of Akabane and the other teratogenic viruses is related to the area of distribution of C. brevitarsis in the north and east of the country. Climatic factors influence the seasonal activity and geographic range of the vector populat ion. In addition, the presence of C. brevitarsis has b e e n reported f rom Papua N e w Guinea, the So lomon Islands, N e w Caledonia and Fiji.

84 Rev. sci. tech. Off. int. Epiz., 19 (1)

Pathology

T h e destruction of neuronal cells appears to b e a significant feature of the pathogenesis of central nervous system lesions due to viral infection. The disease has b e e n reproduced in ruminants in Japan and Australia. Inoculated animals seroconvert rapidly after a short subclinical viraemia. Infection is of consequence only if ruminants are pregnant and are not protected b y previous specific neutralising antibodies. Akabane, Aino, Douglas and Tinaroo viruses have b e e n s h o w n to cross the placenta. Experimentally-infected ewes b e c a m e viraemic, with virus replication in the trophoblastic cells of the placenta. Subsequently, foetal membranes and tissues were infected with a tropism for immature cells of the foetal central nervous system and skeletal muscle , inducing necrotising encephalomyeli t is and polymyositis. In surviving foetuses, multiple abnormalities may b e descr ibed as arthrogryposis, hydranencephaly, microencephaly, cerebellar hypoplasia, irregular neuromuscular deve lopment with atrophy and neural degeneration of muscles and de fo rmed skele ton. The severity of brain damage can range from microscopic to severe cavitation atrophy and eventually a comple te absence of the cerebrum. Spinal cord lesions are always present. Late gestational infections cause inflammation in the brain and spinal cord, premature birth, or foetal death with stillbirth or abortion. Without assistance, females unable to deliver de fo rmed full-term foetuses may die. Many calves with little more than the brain s tem intact may b e b o m alive. Affected neonates are non-viable (7).

A correlation was found b e t w e e n the gestational age of the infection and birth defects. The earlier foetal infection occurs in gestation, the m o r e severe the lesions, reflecting the lack of foetal immunocompe tency in the earlier stages of pregnancy. Infection from w e e k eleven to fourteen after concept ion caused hydranencephaly or microencephaly, from w e e k fifteen to twenty-four, arthrogryposis, and from w e e k twenty-five to thirty-three, pol ioencephalomyeli t is . The infection of embryonated ch i cken eggs is also used as a convenient m o d e l for experimental studies. Induced lesions are very similar to those found in congenital abnormalities in calves with a variety of malformations (26).

Diagnosis

Diagnosis is per formed b y serology, viral isolation and antigen detection. The damaged foetus or neonate d o e s not normally contain virus. Viruses are isolated from the b l o o d of healthy cattle, and rarely f rom affected cattle or foetuses (50). T h e b l o o d is inoculated to mosqui to cells, or via the intracerebral route, into suckling mice . T h e v ims may b e adapted to various mammal ian cell cultures including Vero or b a b y hamster k idney (BHK)-21 cells. An ELISA can b e used for specific identification of viruses (5). Virus-specific neutralising tests are necessary to establish the specific aetiology.

Prevent ion The only risk factor relevant to disease is pregnancy. Killed vaccine against Akabane v ims has b e e n p r o d u c e d and has b e e n used to prevent disease b y protecting susceptible cows during pregnancy in areas at great risk. However , this is not always justified economical ly.

Nairobi sheep disease Nairobi s h e e p disease (NSD) is a viral disease w h i c h is one of the mos t pathogenic for s h e e p in East Africa. In 1910, the cause was identified from s h e e p in quarantine in Nairobi, Kenya, as a filterable agent. The v ims is transmitted trans-stadially and transovarially b y Rhipicephalus appendiculatus ticks. The infection in sheep , and to a lesser extent in goats, causes an acute haemorrhagic gastroenteritis resulting in mortality rates exceeding 90% in susceptible populations. The disease has b e e n observed in Kenya, Uganda, Somalia, Rwanda and Tanzania (10). Outbreaks are often related to movement s of non- immune herds in endemic areas. The v ims be longs to the genus Nairovirus and is n o w recognised to b e indistinguishable from Ganjam, a v ims isolated f rom Haemaphysalis intermedia t icks in India and Sri Lanka, wh ich causes a similar disease in s h e e p and goats (34) . Occasional cases of h u m a n disease, with pyrexia, h e a d a c h e and abdomina l pains, have b e e n descr ibed in laboratory workers .

Pathology T h e disease in sheep is characterised b y a febrile illness with p e a k temperature reaching 41°C two to three days after onset, and persisting for up to eight days. Animals stand with the h e a d d o w n and are disinclined to move . Symptoms include anorexia, injection or cyanosis of the conjunctiva, a rapid respiratory rhythm, and somet imes a nasal discharge. Mucous and b lood- t inged diarrhoea appear one to three days after onset, with abdominal pain. Death can occur at any stage after the onset of the disease. In pos tmor tem examination of early deaths, unspecific congestion of mos t organs and petechial and ecchymot ic haemorrhages have b e e n descr ibed (11).

Epidemiology Sheep and goats are the principal hosts of the disease. In areas of Kenya, Tanzania and Uganda where R. appendiculatus is c o m m o n , several clinical forms have b e e n observed, and NSD antibodies have b e e n detected in s h e e p sera. In enzootic areas, rapid immunisation of young animals may occur while the animal is protected b y maternal antibody and chal lenged b y tick exposure. Movements of susceptible animals in endemic areas result in clinical cases and death. In experimental infections, susceptibility differed according to the animal species. East African hair sheep are highly susceptible with mortality reaching 75% compared to 30%-40% for s o m e imported sheep . Cattle and other domest ic animals are not susceptible to the vims. No clinical cases of NSD have b e e n identified in wildlife, and no antibodies have b e e n recorded in wild ruminants.


The trae range of NSD remains to b e established. The geographic distribution of the disease includes Kenya (highland plateau and coastal regions), Uganda, Rwanda (Lake Kivu), Ogaden in Somalia, and northern Tanzania. The disease m a y also exist in the south-east of Ethiopia. S o m e serological NSD cross-reactions in s h e e p sera f rom Namibia and Botswana have b e e n observed. The distribution of R. appendiculatus t ick populat ions is influenced b y the climate, in particular the temperature and the intensity and duration of the rainfall. Variations in R. appendiculatus t ick populat ions with a seasonal b reed ing cycle, as obse rved in south Tanzania, Zambia and Mozambique , could act as a biological barrier to NSD virus transmission. A temperature range of 19°C-30°C and humidity over 4 5 % are necessary for tick maturation (10) . T h e distribution also includes India and Sri Lanka w h e r e the virus was recovered f rom H. intermedia ticks and, in sporadic cases, f rom animals. Introduction of the disease from India to East Africa, via s h e e p and goats, has b e e n suggested.

The persistence of the virus in tick populat ions has b e e n demonstrated. Vertically infected R. appendiculatus larvae remained infective 245 days after hatching, n y m p h s 348 days after moulting, and adults 81 days after incubation (10). T h e virus was also isolated from Amblyomma variegatum. This species is capable of transmitting the virus trans-stadially, but is a far less efficient vector. Another t ick species , R. pulchellus, may occasionally transmit the virus.

Diagnosis The virus can b e isolated from the plasma of infected animals during the febrile phase and f rom the sp leen and mesenteric lymph n o d e s after death. T h e virus m a y b e recovered b y inoculating BHK-21 c lone 13 cells, w h i c h p roduces a cytopathogenic effect within two to four days. Viral antigen can b e de tec ted b y immunof luorescence 12 h - 2 4 h post inoculation. Vero cells are repor ted to b e less sensitive to viral infection. T h e virus can also b e isolated in suckling mice following inoculation b y the intracerebral or intraperitoneal route. Other techniques are available, such as the direct detection of viral antigen in tissues, amplification of fragments of the viral g e n o m e using suitable primers and amplification by RT-PCR.

Prevent ion Epidemics of NSD are caused b y the introduction of a non- immune popula t ion into endemic areas, the introduction of infected ticks into a receptive area, or ecological changes which extend the t ick vector distribution into non-endemic areas. T ick control has b e e n at tempted, but is difficult to maintain and is very costly.

Other bunyaviruses of animal importance In 1987, Cache Valley virus, a bunyavirus m e m b e r of the Bunyamwera serogroup, was descr ibed as a causative agent of disease in s h e e p in Texas, United States of America (USA) (12). T h e clinical, pathological and immunological features were similar to those repor ted for Akabane virus infection.

T h e virus is endemic in North America (Canada, USA and Mexico) and has b e e n isolated from several mosqu i to species , including Culiseta inornata, A. quadrimaculatus,Ae. sollicitans and Ae. albopictus.

Experimental infections in s h e e p and goats provide signs of central nervous system disturbances. Cache Valley virus causes embryonic and foetal death, stillbirth and congenital malformations, arthrogryposis and hydranencephaly. T h e disease has b e e n r ep roduced b y experimental infection (8). Human infections are not u n c o m m o n al though the effect o n pregnancy is unknown .

In experimentally infected ewes , other bunyaviruses, for example , Main Drain f rom the Karri serogroup, and San Angelo and La Crosse f rom the California serogroup, have b e e n s h o w n to induce teratogenic effects identical to those descr ibed in ovine infections by Cache Valley and Akabane viruses (13). Main Drain is also associated with encephalomyeli t is in horses . Viruses f rom the California group are transmitted b y mosqui toes and are distributed primarily in North America. These viruses generally p roduce subclinical or mi ld infection associated with central nervous system involvement in humans . La Crosse virus, transmitted mainly b y Ae. triseriatus, induces classical acute encephalitis in children, somet imes with sequelae , such as epilepsy, occasionnaly leading to death during the acute phase (20) . In ch ipmunks and squirrels, the natural hosts of La Crosse virus, the virus p roduces non-symptomat ic infection with a viraemia, thereby allowing b lood-suck ing mosqui toes to b e infected. Domest ic rabbits are used as sentinels for surveillance (33) . San Angelo virus, wh ich was primarily isolated from Anopheles mosqu i toes in 1958 in Texas, has not b e e n associated with clinical illness in humans and the natural host remains unknown . Large gaps of knowledge remain with regard to the real importance of these diseases in local l ivestock.

Other bunyaviruses have s o m e importance for h u m a n publ ic health, a l though natural infections of wild and domest ic animals have not b e e n associated with disease. Wi ld rodents and marsupials are implicated as the main vertebrate hos ts of Group C bunyaviruses w h i c h induce benign febrile illness in humans and are mostly distributed in the Amazon region of South America. In Africa, bunyaviral fevers with h e a d a c h e and arthralgia have b e e n reported in humans but n o natural disease has b e e n demonstrated in animals.

Filoviridae Introduction Filoviridae are the causative agents of diseases with h igh mortality in primates. T w o b iochemica l ly and genetically distinguishable types exist, namely: Marburg and Ebola. Marburg virus was first isolated during an outbreak in Europe in 1967, and Ebola virus in 1976 as the causative agent of two


different outbreaks in the Sudan and the Democratic Republic of the Congo . Transmission b y intimate contact be tween individuals s eems to b e a major route of infection. Another Ebola subtype was identified in 1989, in a quarantine facility in Reston, USA, among dying m o n k e y s impor ted f rom the Philippines. T h e natural reservoir of these viruses remains a mystery (29) .

Aetiological agents T h e virions of filoviruses have a particular bacill iform

morpho logy with filamentous particles of 800 n m to

1,000 n m in length and a uniform diameter of 80 n m , hence

the n a m e of the viral family. The virus possesses a hel icoidal

capsid, an enve lope and seven major structural proteins. T h e

genome is c o m p o s e d of a single negative strand of linear RNA

which requires a polymerase for transcription before

replication (15) .

Epidemiology In 1967, in Marburg, Germany, and in Belgrade, Yugoslavia, ep idemics resulted in thirty-one cases of infection with Marburg virus, including six secondary cases and seven deaths, among laboratory workers in contact with African green m o n k e y s (Cercopithecus aethiops) f rom Uganda, or with m o n k e y primary cell culture suspensions. Sporadic cases were reported in humans from Zimbabwe in 1975, and Kenya in 1980 and 1987 (29). A main focus of Marburg disease was confirmed in May 1999, in the north-eastern province of the Democratic Republic of the Congo, with tens of deaths, mainly among miners working in a gold mine in the Durba area.

Ebola virus was first descr ibed in Central Africa in 1976. An outbreak occurred in July 1976 in south-western Sudan (Nzara, Maedi) and two months later in Yambuku , in the northern region of the Democratic Republic of the Congo , with very high mortality (318 cases, 280 deaths) (25). The origins of primary contamination remained unknown, but poor sanitary condit ions in the local hospitals l ed to the spread of the virus. In 1994, in Côte d'Ivoire, an ethologist working in the Taï National Park no ted several deaths in a t roop of chimpanzees . She contracted the disease and symptoms c o m m e n c e d with fever, progressing to diarrhoea and rash, eight days after performing an autopsy o n a chimpanzee. High mortality in ch impanzee colonies of the surveyed area was reported in N o v e m b e r 1992 , and in November 1994 w h e n 2 5 % of a group of forty-three wild ch impanzees d ied or disappeared (17) . Ebola infection was identified in one of these animals (53) . In 1995, in Kikwit, in the Bandundu Province of the Democratic Republic of the Congo, a large outbreak was recorded in the local hospital, resulting in 244 h u m a n deaths among 315 cases. T w o separate ep idemics were also recorded in Gabon in 1996 (25). Following transportation, preparation and cook ing for consumpt ion of a dead ch impanzee from the forest, thirty-seven p e o p l e from Mayibout village were infected, twenty-one of w h o m d ied (57%) . Twenty-one of the patients

h a d direct contact with the dead animal or organs, and sixteen

cases occurred through person-to-person transmission.

Another ep idemic was reported a few months later in the

M a k o k o u area. The index case was a hunter w h o d ied in

hospital.

In N o v e m b e r 1989, an epizootic was reported in a primate import quarantine facility in Reston (Virginia, USA) involving numerous deaths in cynomolgus m o n k e y s (Macaca

fascicularis). T h e m o n k e y s h a d b e e n impor ted f rom the Philippines, directly or via Amsterdam, before reaching the USA. A virus closely related to Ebola was isolated from m o n k e y s and n a m e d Ebola subtype Reston. All the m o n k e y s in the facility were euthanised. F r o m January to March 1990, a n e w epizootic occurred among m o n k e y s of the same origin. Animals were not euthanised and the virus propagated f rom r o o m to r o o m , probably b y droplet contact. Four h u m a n infections were r ecorded among workers from the facility without any clinical symptoms , suggesting an absence of virulence in humans (25). A single holding c o m p a n y was the source of these different shipments of m o n k e y s from the Philippines. Evidence was found of an epizootic among m o n k e y s in 1990, in the facility in the Philippines, with filoviral antigen detected in 52 .8% of m o n k e y s w h i c h died during a surveillance per iod of 2.5 months (22). A further outbreak was repor ted in 1992 in Sienna, Italy. The virus was isolated from three m o n k e y s from the same holding c o m p a n y in the Philippines; n o h u m a n infections were recorded . T h e animals f rom the Philippines were caught in the wild, h e n c e the virus could b e reintroduced into the facility at any time. Other m o n k e y s impor ted to the USA in 1993 h a d Ebola Reston antibodies but n o viral infection. For transportation and importation of non-human primates, a mandatory disease control requirement was necessary. In 1994, the Philippines banned the export of m o n k e y s caught in the wild and instituted a forty-five-day quarantine per iod prior to the export of animals. However, in March 1996, a m o n k e y impor ted from the Philippines d ied in a quarantine facility in Texas and this animal and one other were found to b e positive for Ebola Reston. All animals from the same quarantine cohor t were destroyed (39). In the Philippines, surveillance was initiated among five monkey-breed ing and export facilities. In one facility, one animal was reported to b e acutely infected, and three m o n k e y s and one animal handler tested positive for Ebola Reston antibodies (28).

Pathology In African green m o n k e y s experimentally infected with Ebola

subtype Zaire or Marburg virus, the incubation pe r iod is four

to sixteen days. During the incubation per iod, the virus

replicates primarily in monocytes and macrophages , then in

the liver, spleen, lymph nodes and lungs. Wi th the onset of

the disease, the severity of damage increases with diffuse foci

of necrosis in the parenchyma, and is directly correlated with

the presence of large numbers of virions (16, 23 , 37) . Little

inflammatory response is observed in lesion sites.

Thrombocytopenia and microcirculatory disturbances are


descr ibed as capillary stasis and formation of small thrombi . Dystrophic changes in endothel ial and epithelial cells of the lungs and extensive destruction in the liver, sp leen and adrenals are reported. Moderate elevation of alanine aminotransferase and high elevation of aspartate aminotransferase in se rum indicates other target sites bes ides hepatocellular dysfunction. S o m e features, such as the responses of b l o o d clotting and vascular permeabil i ty appear to b e species-specific in the m o n k e y (40). T h e subtypes Ebola Sudan and Ebola Reston are less virulent and cause a self-limiting infection in m o n k e y s (16, 18, 23) .

The reservoir of filoviruses The distribution of Marburg virus appears to b e limited principally to one region of Africa, comprising Kenya, Uganda and the north-east of the Democratic Republic of the Congo. Ebola virus has b e e n recovered in the Democratic Republic of the Congo , southern Sudan, G a b o n and Côte d'Ivoire, f rom infected dying m o n k e y s in two outbreaks . In addition, the Reston ep i sode indicated the presence of filoviruses in m o n k e y s in Asia. T h e epizoot ics of Ebola Reston and the ep idemics of Ebola and Marburg raise the quest ion of whether non-human primates might b e the primary reservoir. Persistence of filoviruses in m o n k e y s has never b e e n demonstrated and the h igh mortality rate among m o n k e y s suggests that these animals could not act as a reservoir of the filoviruses. Furthermore, Marburg virus has never b e e n isolated from wild m o n k e y s , and all m o n k e y s w h i c h have b e e n experimentally inoculated with Marburg virus d ied (21) . Chronic infection of a m a m m a l is nevertheless the likely mechan i sm for survival of these viruses in nature. In Kikwit in 1995, the putative index case was a farmer w h o h a d recently excavated a local charcoal pit. An extensive search to reveal a potential reservoir or vector in the area was unsuccessful. In a hypothetical transmission cycle, bats are cons idered the most likely vertebrate hosts of viruses (29) . F e w studies have b e e n under taken in this particular field. S o m e fruit and insectivorous bats suppor ted replication of the virus without clinical symptoms (48) . A recent publication identified filoviral RNA b y genetic amplification in s o m e rodents in the Central African Republic. If such findings are confirmed, this would b e the first evidence of a naturally infected rodent (31).

Diagnosis In the case of suspected filoviral disease in primates, handling and autopsy must b e conduc ted following strict guidelines. Specimens (b lood , sk in b iopsy and tissues) must b e sent for diagnosis to a laboratory with biosafety level 4 facilities, following the recommenda t ions of the Wor ld Health Organization. Viral isolation or identification are necessary for epidemiological investigations. As an alternative, formalin specimens are suitable as non-infectious material and are simple to transport.

Prevention and control Risk of exposure to filoviruses mainly concerns p e o p l e in contact with m o n k e y s caught in the wild, or workers in quarantine facilities. Transmission by aerosol has b e e n demonstra ted for Ebola Reston and Marburg viruses. Filoviruses have b e e n s h o w n to survive for a few days o n contaminated surfaces at r o o m temperature. Infectious virions can b e inactivated b y heating at 60°C for 30 minutes or b y using an appropriate amount of lipid solvent, or disinfectants such as fo rmaldehyde or hypochlor i te (15) . A reduct ion in the use of m o n k e y s in the pharmaceutical industry for vaccine product ion and controls is encouraged. For transportation and importat ion of non -human primates, a mandatory disease control requirement is necessary in s o m e countries. Given that, in 1994, the Philippines banned the export of m o n k e y s caught in the wild and instituted a forty-five-day quarantine requirement prior to exporting animals, the 1996 ep i sode suggests p o o r sanitary and containment condit ions in the export facilities. Further investigations o n the pathology, virulence and eco logy of filoviruses are necessary to improve understanding of the cycle and to provide adequate preventive measures .

Conclusion Many aspects of bunyaviral diseases are misunderstood, or unknown . No reliable small rodent m o d e l exists to study the pathogenesis of viruses causing teratogenic or abortogenic effets. La Crosse, Main Drain and San Angelo viruses were found to induce teratogenic effects in experimental infections of sheep . However , whether such pathogenicity occurs in wild or domest ic animals in nature is not k n o w n . Rift Valley fever remains an emerging disease in Africa and is related to ecological changes. On account of the substantial e c o n o m i c losses w h e n an outbreak occurs, active research o n vaccine is n e e d e d to prevent disease in animals and frequent transmission to humans . In contrast to RVF, NSD virus is restricted to a specific populat ion of ticks in East Africa and d o e s not lead to disease in humans . Although Akabane and related viruses have a wide geographic distribution, the e c o n o m i c impact of the disease is not k n o w n and requires further study. The recent ep idemics of Ebola virus in Africa and Ebola Reston in m o n k e y s from the Philippines have attracted attention. Extensive studies have b e e n under taken to understand m o r e fully the eco logy and the transmission of filoviruses and to avoid infections; however , the reservoir remains to b e determined.

•

8 8 Rev. sci. tech. Off. int. Epiz., 19 (1)

Infections dues aux virus appartenant aux familles des Bunyaviridae et des Filoviridae

H. Zeller & M. Bouloy

Résumé

La fièvre de la Vallée du Rift est la principale maladie animale due à des bunyaviridés en Afrique. Transmis par les moustiques, le virus est à l'origine, chez l'animal, d'avortements et d'une mortalité élevée des jeunes, et chez l'homme, de fièvre hémorragique. Il existe des vaccins contre ce virus mais leur utilisation est limitée en raison de leurs effets secondaires ou de l'insuffisance de la protection qu'ils confèrent; les recherches doivent donc être poursuivies pour améliorer la qualité de ces vaccins ou pour mettre au point de nouveaux vaccins plus efficaces. La maladie de Nairobi est transmise par les tiques. La maladie est endémique en Afrique de l'Est et des cas sporadiques sont signalés en Inde et au Sri Lanka. D'autres virus, transmis par les moustiques et les mouches Culicoides spp., sont tératogènes pour les bovins et les ovins, notamment le virus d'Akabane et d'autres virus apparentés qui sévissent en Asie, en Australie et au Moyen-Orient et le virus de la Vallée Cache en Amérique du Nord. Le virus de Marburg et le virus Ebola, du genre Filovirus, sont à l'origine d'épidémies très meurtrières en Afrique centrale ; certains cas ont été attribués à des contacts avec des singes. Un autre virus appartenant au sous-type Ebola a été décrit pour la première fois dans un établissement de quarantaine aux États-Unis d'Amérique chez des singes cynomolgus (Macaca fascicularis) en provenance des Philippines. Le réservoir de ces virus demeure inconnu.

Mots-clés Bunyavirus - Fièvre de la Vallée du Rift - Filovirus - Maladies animales - Nairovirus -Phlebovirus - Santé publique - Singes - Virus de Marburg - Virus Ebola - Zoonoses.

Infecciones por virus de las familias Bunyaviridae Y Filoviridae H. Zeller & M. Bouloy

Resumen

La fiebre del Valle del Rift es la principal enfermedad causada por bunyavirus que afecta a los animales africanos. El virus, transmitido por mosquitos, provoca abortos y la muerte de animales jóvenes, así como fiebres hemorrágicas en el ser humano. Pese a que existen vacunas contra este virus, su utilización no está muy extendida a causa de los deletéreos efectos que a veces conllevan y de la insuficiente protección que confieren, lo cual justifica nuevas investigaciones que intenten mejorar las vacunas existentes o crear otras nuevas. La enfermedad de Nairobi, transmitida por garrapatas, es endémica en África Oriental, y esporádicamente se declaran también casos en la India y Sri Lanka. Otros virus transmitidos por mosquitos o moscas Culicoides spp. son teratogénicos en bovinos y ovinos, como es el caso del virus Akabane y otros virus afines en Asia, Australia y Oriente Medio y del virus del Valle Cache en Norteamérica. Los virus Marburg y Ebola, del género Filovirus, han dado lugar a epidemias en África Central, acompañadas de elevadas tasas de mortalidad en el hombre. Algunos casos han sido relacionados con el contacto con monos. En una instalación de

Rev. sci. tech. Off. int. Epiz, 19 (1) 89

cuarentena en Estados Unidos de América se describió por primera vez la presencia de otro virus del subtipo Ebola en monos cynomolgus (Macaca fascicularis) procedentes de las Filipinas. El reservorio de esos virus constituye por ahora un enigma.

Palabras clave Bunyavirus - Enfermedades animales - Fiebre del Valle del R i f t - Filovirus - Phlebovirus -Monos - Nairovirus - Salud pública - Virus Ebola - Virus Marburg - Zoonosis.

•

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infections by viruses of the families bunyaviridae and filoviridae

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