Old World alphavirus infections in animals

Introduction

Alphaviruses in the family Togaviridae are important emerging and re-emerging pathogens of humans and animals. These viruses can be divided into the New World alphaviruses (see Equine encephalitides caused by alphaviruses in the Western Hemisphere) that are associated with encephalitis in horses, humans and certain other animals in the Americas, and the Old World alphaviruses, which are mostly believed to be associated with arthralgia in humans, with less data available as to their importance in animals. Recent reports of infections in horses with Old World alphaviruses such as Middelburg virus (MIDV) and Sindbis virus (SINV) in South Africa and Ross River virus (RRV) in Australia have renewed interest in the potential of these viruses as animal pathogens. This chapter focuses on the lesser known alphaviruses, in particular the Old World alphaviruses and their role in animal diseases.

Aetiology and epidemiology

The group of alphaviruses includes 31 recognized species grouped into 8 antigenic complexes (Figure 1) based on their serological cross-reactions: Barmah Forest, Eastern equine encephalitis, Middelburg, Ndumu, Semliki Forest, Trocara, Venezuelan equine encephalitis and Western equine encephalitis complexes. These viruses have a very wide geographic distribution.^{21, 75} (see Table 1 Equine encephalitides caused by alphaviruses in the Western Hemisphere). Following the full genome sequencing of all members of the alphaviruses, it has been suggested that the alphaviruses emerged in the southern oceans from marine animals, with subsequent spread to terrestrial vertebrate hosts and mosquito vectors. This enabled them to expand their range throughout the Old and New World, where reintroductions between continents have also occurred.¹⁸ The molecular biology of the genus is described in detail elsewhere (see Equine encephalitides caused by alphaviruses in the Western Hemisphere). Although much less is known about the pathogenic potential of the Old World viruses for animals, reports on human and animal disease, reservoir hosts, vectors, and laboratory investigations are summarized in this chapter.

Figure 1 Phylogenetic tree of representative isolates of all alphavirus species in the genus a Alphavirus, family Togaviridae as reproduces from the ICTV website (https://talk.ictvonline.org/ictv-reports/ictv_online_report/positive-sense-rna-viruses/w/togaviridae). The tree was generated from a conserved region of envelope protein gene nucleotide sequences (2184 nt) using the GTR+I+Γ substitution model and Maximum likelihood method and mid-point rooted. Bootstrap values above 70 generated by 1000 replicates of neighbour-joining tree are indicated next to the main branches.¹⁰

Except for the salmon pancreatic disease virus (SPDV), sleeping disease virus (SDV) and the Southern elephant seal virus (SESV), members of the Alphavirus genus are mainly transmitted by haematophagous arthropods, especially mosquitoes, The salmon pancreatic disease virus has been detected in sea lice (Lepeophtheirus salmonis and Lepeophtheirus macrorhini). The vectors for SESV have not been confirmed as yet.^{18, 37, 76} Studies on the complete genome sequences of all known members of the genus suggest that SPDV and SESV form a separate group to the latter and may be the common ancestor of alphaviruses. The mosquito-transmitted viruses are classified into two well-defined monophyletic groups: New World/encephalitic viruses and the Old World/arthralgia viruses.

The New World viruses consist of the Western equine encephalitis virus (WEEV), SINV, Eastern equine encephalitis virus (EEV) and Venezuelan equine encephalitis virus (VEEV) complexes. Apart from SINV, which occurs worldwide and mostly cause mild disease, the rest of the New World viruses occur in North and South America and are associated with encephalitis in horses and humans (see Equine encephalitides caused by alphaviruses in the Western Hemisphere). Recombination events between EEV and SINV are thought to have given rise to the WEE complex and more pathogenic viruses.⁷

The Old World viruses are grouped into three complexes, namely MIDV, Ndumu (NDUV), Barmah Forest virus (BFV) and Semliki Forest virus (SFV). These viruses are mainly associated with epidemics of polyarthritis in Asia, Australia, Europe, and Africa.¹⁸  Middelburg virus has recently been associated with neurological signs and possibly signs of arthralgia in horses in South Africa.⁷²

Table 1 lists alphaviruses that cluster within the Old World monophyletic groups as well as Sindbis in the WEE group with potential clinical significance in humans and animals.

Table 1: Old World alphaviruses and others outside of the Americas

Western equine encephalitis complex (viruses other than WEEV)

Sindbis virus is the prototype of the genus Alphavirus and was first isolated from Culex  univittatus mosquitoes in 1952 during an epidemic in the Sindbis district near Cairo, Egypt⁴⁶. Ornithophilic Culex spp. mosquitoes are the main vectors but SINV has also been detected in Coquillettidia richiardii, Mansonia africana, Culiseta morsitans, Anopheles hyrcanus and Aedes spp. mosquitoes. The main hosts are birds. It has also been detected in bats, amphibians and rodents. Sindbis virus infection is mainly associated with polyarthritis and a rash in humans. It is present in South Africa, Australia, Saudi Arabia, India, Italy, Greece, Hungary, Portugal, Austria, China, Uganda, Bulgaria, Egypt, New Zealand, Russia, Sweden, Finland, Slovakia, Germany and Israel. The viruses of the syndromes known as Ockelbo, Babanki, Kyzylagach, Karelian and Whataroa fever are all variants of SINV. Limited information is available for these viruses in animals.²⁵ A few cases of fever and encephalitis have been described in horses in South Africa that had co-infections with West Nile virus.⁷³ Recently, SINV has been detected by real-time PCR in species other than horses with fatal neurological infections in South Africa including African buffalo (Syncerus caffer), rhinoceros (Ceratotherium simum), sheep (Ovis aries), giraffe (Giraffa camelpardalis), European wild boar (Sus scrofa), sable antelope (Hippotragus niger) and blesbuck (Damaliscus pygargus phillipsi).⁶⁹

Semliki Forest virus complex

Semliki Forest virus (SFV) was first isolated from mosquitoes in 1942 from Aedes abnormalis mosquitoes caught in the Semliki forest in western Uganda.⁶⁵ Semliki forest virus is present throughout Africa, including in countries in southern Africa, Nigeria, Uganda, Democratic Republic of the Congo (DRC) and Cameroon. Seroprevalence studies in humans in the coastal lowlands of the northern parts of South Africa and in central Mozambique showed positivity rates of 6 per cent and 5 per cent respectively.^{25, 49} Rhesus monkeys (Macaca mulatta) showed no clinical signs when injected with SFV but vervet monkeys (Chlorocebus pygerythrus) presented with fever, while mice developed hind leg paralysis and convulsions followed by death, and rabbits showed fever and paralysis.^{49, 65}

Chikungunya virus (CHIKV) has been one of the most important emerging virus infections of the past decade. It was first identified in Tanzania in 1952 but has since spread across the world, causing outbreaks in Africa, Europe, Asia and the Americas,⁶⁰ In Africa non-human primates such as baboons (Papio ursinus) and bush babies (family Galagidae) are thought to be the reservoirs of the virus. It has been shown that epidemics can be maintained in humans as the only host through transmission by Aedes aegypti and Aedes albopictus mosquitoes.^{13, 42} Following its emergence in the Americas, experimental infection of a range of birds and wild and domestic mammals showed that apart from the big brown bat, Eptesicus fuscus, none of the animals developed detectable viraemia although most seroconverted.⁵

O’nyong-nyong virus (ONNV) was first isolated during an outbreak that started in Uganda in 1959 and spread through Kenya and Lake Victoria’s shores to south- eastern Africa by 1962.⁷⁹ Since then it has caused numerous epidemics in eastern, western and southern Africa including Uganda, Malawi, Kenya, Mozambique, Tanzania, DRC, Senegal and Cameroon.⁵⁹ Following the 1959-1962 epidemic, ONNV activity seemed to have become much reduced.⁴⁵ Nonetheless, in 1978 in western Kenya, ONNV was isolated from a pool of Anopheles funestus mosquitoes.²⁸ Sera from 24 African forest buffalo, 34 African elephants (Loxodonta africana), 40 duikers (Cephalophus and Philantomba spp.), 25 mandrills (Mandrillus sphinx), 32 mountain gorillas (Gorilla beringei beringei), five Grauer's gorillas (Gorilla beringei graueri), two L'Hoest's monkeys (Cercopithecus lhoesti), two golden monkeys (Cercopithecus kandti), and three chimpanzees (Pan troglodytes) sampled between 1991 and 2009 tested positive for antibodies against ONNV by plaque reduction neutralization tests.

Getah virus (GETV) was first isolated in Malaysia in 1955 from Culex gelidus mosquitoes. It commonly infects horses but may also infect pigs. All aspects of GETV infection is described in detail elsewhere (see Getah virus infection).

Mayaro virus (MAYV) was first isolated from the sera of humans who recovered from fever in Trinidad in 1954. The first recorded MAYV epidemic occurred during 1978 in Belterra, Brazil, where virus was only isolated from Haemagogus janthinomys mosquitoes. During the same study antibodies against MAYV were found in 27 per cent of marmoset (Callithrix jacchussera) sera, suggesting that tree-dwelling primates could possibly be the primary vertebrate host.⁴⁰ The absence of human cases after the outbreak and inability to isolate virus from H. janthinomys mosquitoes the following year suggest that the maintenance cycle of MAYV has not yet been identified.⁴⁰

Una virus (UNAV) is the closest genetic relative of MAYV. Limited information is available on the epidemiology and transmission of the virus. It has been isolated from a variety of mosquito species including Psorophora ferox and Psorophora albipes. It is not known whether these mosquitoes are the primary species involved in epidemic transmission and virus maintenance.^{9, 23, 74} Antibodies against UNAV have been found in humans, horses and birds. The risk of developing disease in humans is unknown.^{14, 50, 62}

Ross River virus (RRV) is the most common arbovirus in Australia, with up to 5000 cases reported per year.²⁴ Historical reports correlating with RRV symptoms was made in 1928, although epidemic polyarthritis was only linked serologically to a group A arbovirus (alphavirus) in 1956.⁶³ The virus was subsequently isolated from Aedes vigilax mosquitoes in 1963 and from patients with polyarthritis during an epidemic. The virus is endemic in Australia and Papua New Guinea and epidemics occurred in the South Pacific in 1979 and 1980.²⁴ Serological evidence in humans born after 1980 suggests that the virus circulated between 1980 and 2010 in the Pacific Islands³⁹ and was isolated from tourists with febrile disease visiting Fiji in 2003-2004.³² Ross River virus is associated with peripheral polyarthralgia, arthritis, fever and a rash in humans. The arthritis is due to joint infection and is treated with empirical anti-inflammatory drugs. Although not usually fatal, chronic joint pains may persist for weeks or even months. ²⁴

It is thought that in humans -mosquito transmission may occur during epidemics. Marsupials are generally considered better reservoirs of RRV than placental mammals, which in turn are better reservoirs than birds. High rates of RRV seropositivity were detected in macropods (kangaroos and wallabies) in northern Queensland. It is noteworthy that high levels of circulation of RRV have been reported in the Pacific islands where marsupials do not occur.⁶⁸ At least 40 species of mosquitoes have been implicated as potential RRV vectors. Species most commonly associated with transmission include saltmarsh mosquitoes (Aedes camptorhychus) in southern Australia and Ae. vigilax in the north, while the freshwater mosquito (Culex annulirostris) is found throughout Australia but not in Tasmania.¹¹ Potential reservoir hosts has been identified through virus isolation, experimental infections, vector transmission studies and serosurveys.⁶⁸ In these studies the highest peak viral titres (8 LD₅₀ and viraemia lasting 48 hours) was reported in marsupial mouse (Antichinus spp.) compared to rabbits (Oryctolagus cuniculus) (4.75 LD₅₀, viraemia lasting 48 hours). ⁷⁷  Kay et al.³⁰ infected a wide range of species and reported the highest viraemia in horses (Equus caballus) at 6.3 SMIC (suckling mouse intercranial injection), compared to black ducks (Anas rubripes) that developed a peak titre of 1.8 SMIC, while viraemia in grey kangaroos (Macropus giganteus) attained moderately high levels but lasted the longest. Only pigeons (Columba livia domestica), cats (Felis catus) and dogs (Canis lupus familiaris) did not develop detectable viraemias. Horses developed the highest viraemia with the longest durations (112 hours) and were able to reinfect 11 per cent of vectors. This was comparable to little corellas (Cacatua sanguinea) (2.3 SMIC, viraemia 50 hours) (reinfect 14 per cent of an unknown number of vectors) when susceptible Cx annulirostris vectors were used to feed on infected hosts.³⁰ Virus has been isolated commonly from horses, and more rarely from agile wallabies (Macropus agilis) and birds.^{16, 56, 78} The seroprevalence in marsupials was greater than in placental mammals and birds (44 per cent, 16 per cent and 0 per cent respectively), with the interquartile range greatest in the marsupial group (5–75 per cent) and smallest in the bird group (0–6 per cent). Seropositive birds included black ducks (Anas superciliosa) and little corellas. For placental mammals, the highest seroprevalence was observed in red foxes (Vulpes vulpes), followed by rabbits (Oryctolagus cuniculus). All of the following marsupial species  tested positive to RRV: the eastern bettong (Bettongia gaimardi), eastern barred bandicoot (Perameles gunnii),  long-nosed potoroo (Potorous tridactylus), northern nail-tail wallaby (Onychogalea unguifera), Tasmanian devil (Sarcophilus harrisii) and the tiger quoll (Dasyurus maculatus).⁶⁸    

Barmah Forest virus complex

Barmah Forest virus (BFV) was first isolated in 1974 from Culex annulirostris mosquitoes collected in the Barmah Forest, Australia.⁴⁷ Since then, it has been isolated from various mosquitoes namely Aedes camptorhynchus and Aedes vigilax, and from the midge Culicoides marksi.^{15, 27, 61} Vertebrate hosts of BFV are presently unknown.⁶

Middelburg virus complex

Middelburg virus (MIDV) is currently the only virus in this complex and was first isolated in 1957 from Aedes mosquitoes following a disease outbreak, later shown to be Wesselsbron disease, in sheep in the Eastern Cape Province, South Africa.³³ It was initially thought to be non-pathogenic until the virus was isolated from the spleen of a horse in Zimbabwe that died of signs resembling African horse sickness (AHS) in 1993.³ Since its first isolation, MIDV has been isolated most commonly from floodwater-breeding Aedes mosquitoes and occasionally from Culex theileri in South Africa and Zimbabwe.²⁹ It was also found in Aedes caballus and Mansonia africana.²⁵ Middelburg virus has been isolated in several African countries including South Africa, Cameroon, Zimbabwe, Kenya, Senegal and the Central African Republic.²⁵ Seroprevalence surveys conducted in KwaZulu-Natal Province, South Africa demonstrated antibodies in goats, cattle, sheep and humans.^{35, 66} As part of investigations of the role of arboviruses as a cause of febrile and neurological disease in horses in South Africa, blood and tissue specimens of 623 horses (346 horses with neurologic disease and 277 suffering from febrile illness) submitted over a period of 6 years (2008-2013) were screened for alphaviruses using a genus-specific real-time PCR. A total of 8 SINV and 44 MIDV infections were detected including dual arbovirus infections in 3 SINV-infected and 5 MIDV-infected horses. Co-infection with WNV likely contributed to fatal outcome in some of the SINV-infected horses. Many of the uncomplicated MIDV-positive horses manifested neurologic disease. The authors concluded that Old World alphaviruses may cause febrile and neurologic disease in horses similar to that produced by New World alphaviruses.⁷² In subsequent studies (2010-2018) neurological infections and death were described in species other than horses. A total of 32/608 (5.3 per cent) alphavirus positive brain infections were identified (9 SINV and 23 MIDV). These MIDV-positive cases included rhinoceros, African buffalo, cattle (Bos taurus), warthog (Phacochoerus africanus), lion (Panthera leo), birds (e.g. dove and blue crane), sable antelope and waterbuck (Kobus ellipsiprymnus), while SINV was detected in African buffalo, sable antelope, rhinoceros, giraffe, European wild boar, sheep, blesbuck and a genet (Genetta spp.).  Co-infection with MIDV/SINV was reported in a genet while 2 rhinoceros had co-infections with MIDV, Shuni virus and equine encephalosis virus (EEV). A domestic bovine and an African buffalo had MIDV/WNV co-infections. A total of 20/23 MIDV cases (87.0 per cent) were fatal vs 100 per cent in SINV-positive animals in this study, all of which were submitted as post-mortem specimens. Middelburg virus was detected in the central nervous system of 14/23 animals, in visceral organs and blood in 6/23. Neurological manifestations prior to death were observed in all clinically sick animals (22/22) infected with MIDV.⁶⁹

Ndumu complex

Ndumu virus (NDUV) was originally isolated from a pool of Mansonia uniformis mosquitoes in northern KwaZulu-Natal, South Africa.³⁴ The virus appears to circulate throughout Africa. Although antibodies against NDUV have been found in human sera from several African countries, no human or animal illness has been associated with infection with this virus. From studies done in Uganda it has been suggested that pigs may be a host for NDUV.⁴⁸ Ndumu virus has been isolated from various mosquito species including Culex pipiens, Ae. mcintoshi/circumluteolus, Ae. ochraceus, Ae. tricholabis, Cx. rubinotus, Ae. dalzieli, Ae. vexans, Anopheles rufipes, An. ziemanni and Cx. poicilipes.  ^{12, 44, 53, 55}

Old world alphavirus infections: General remarks

Arthritogenic alphaviruses mostly cause an acute disease, with the onset of symptoms appearing 3-10 days post-infection with a short viraemic stage of 4-7 days. The most common symptom of alphavirus infection in humans is arthritis with pain and swelling resolving after a few days.^{26, 31, 38} Limited information is available regarding the pathogenesis involved in alphavirus-induced arthritis and arthralgia.⁴¹

Following a mosquito bite, alphaviruses⁵⁴ result in viraemia and leukopenia in the acute phase of infection. It has been suggested that primary virus replication occurs in leukocytes³⁸ as well as in the liver and spleen.⁵² Muscles, bones and joints may become affected in the acute phase of disease.^{2, 19, 26, 67}

Viraemia usually subsides within five days post-infection and antibodies are typically produced within 4-8 days, indicating clearance of the virus.⁵² Alphaviruses are cleared by the immune system but arthralgia may last for a few weeks or even years.⁷⁵

Old World alphaviruses most commonly cause fever, rash, nausea, back pain, photophobia and arthralgia in humans.  During the early phase of infection, muscle pains, headache and malaise can be experienced followed by grave manifestations such as purpura, melaena, petechiae, haematemesis and bleeding of the gums in severe CHIKV, MAYV and ONNV infections.^{31, 51, 58} The joint manifestations are usually severe and debilitating, affecting particularly the interphalangeal joints, ankles and wrists. These symptoms are similar to other inflammatory joint diseases thus making it difficult to differentiate clinically.⁴²

Horses and other animals may present with a wide variety of clinical signs including neurological signs, fever, stiffness, depression, swollen limbs, hyperreactiveness, paresis, recumbency, seizures, paralysis, ataxia, abortion, icterus, nasal discharge, urticarial rash, oedema of the hind limbs, swelling of the submandibular lymph nodes, lymphocytopenia and death.^{1, 3, 72, 73}

Meningoencephalitis characterized by perivascular cuffing, glial nodules, and diffuse gliosis of brain and spinal cord tissue have been associated with SINV and MIDV infections in horses.⁷²

Although CHIKV has not been associated with animal disease, in human neonates with CHIKV infection scattered white matter lesions, parenchymal haemorrhages and early cytotoxic oedema have been identified with pathological brain magnetic resonance imaging.⁵⁸

During the first five days of illness, RT-PCR or viral culture using in vitro cell lines (mosquito or Vero cell lines) or animal inoculation can be performed to make a diagnosis of alphavirus infections.^{4, 19, 36} Numerous nested and hemi-nested RT-PCR assays have been designed for the detection of members of the genus Alphavirus.^{20, 22, 64, 72}

Following the acute stage of infection, serum should be collected 2 weeks apart and  evaluated for anti-IgM or a rise in anti-IgG antibodies by immunoassays such as enzyme-linked immunosorbent assays, immunofluorescence assays,  and haemagglutination inhibition assays (HAI).^{4, 17, 36, 57}

Getah virus is the only Old World alphavirus that has a vaccine available for horses (see Getah virus infection), although several clinical trials are underway for RRV and CHIKV vaccine candidates in humans.^{8, 43, 80} Treatment includes rest, antipyretics, fluids and analgesics. Severe joint pain may be reduced by corticosteroids, physiotherapy and non-steroidal anti-inflammatory drugs.^{70, 71}

The control of mosquito vectors is discussed in the chapter dealing with New World alphaviruses infections (see Equine encephalitides caused by alphaviruses in the Western Hemisphere).

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