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Israel Journal of Veterinary Medicine  Vol. 70 (2)  June 2015 3 Avian Flaviviruses
A New Look at Avian Flaviviruses
Davidson, I.
Division of Avian Diseases, Kimron Veterinary Institute, P.O. Box 12, 50250, Bet Dagan, Israel.
ABSTRACT
Te faviviruses are important pathogens of wild birds, domestic poultry and humans, and several members are
zoonotic. Te review presents an update of the classifcation of this family of avian faviviruses, describing their
emergence, hosts and major disease features, dissemination patterns and control, as well as their molecular
classifcation and genetic relatedness. A new perspective, based on the molecular identity of TMEV and
BGAV throughout the entire genome, presents an innovative look at avian faviviruses ofering a global
perceptive on the presence of these avian faviruses and on the present view that TMEV exists only in Israel.
Terefore, we suggest renaming TMEV and BGAV by a unifed name, Avian Meningoencephalitis Virus
– AMEV.
Keywords: Avian Flaviviruses; Turkey Meningoencephalitis virus (TMEV); Bagaza virus
(BGAV)
INTRODUCTION
Te faviviruses (genus Flavivirus) are important patho-
gens of wild birds, domestic poultry and humans, and
several members are zoonotically important. Tese viruses
are distributed worldwide and cause widely diverse dis-
eases varying from mild viral symptoms to severe and
fatal hemorrhagic and neurological diseases. About 70
favivirus species are known today, 40 of which cause
infection in humans. Te genus presents major concern
due to its rapid rate of evolution, leading to the emergence
of new viruses. Te emergence of novel faviviruses viruses
in wild birds and in poultry during the last years in several
continents is a live refection of that phenomenon, rais-
ing the necessity to reconsider our acquaintance with the
favivirus family.
Te review presents a “who’s who” in avian faviviruses,
describing their emergence, hosts and major disease features,
dissemination patterns and control, as well as their molecular
classifcation and genetic relatedness. A new look at favivi-
ruses ofers a global perceptive on the presence of the avian
faviruses.
WHO’S WHO IN AVIAN FLAVIVIRUSES,
DISEASES AND HOSTING AVIAN SPECIES?
During the year 2010 several avian faviviruses brought
renewed attention in several countries, attracting global
interest.
Turkey Meningoencephalitis Virus (TMEV)
Te virus was frst described by Komarov and Kalmar in
1960 (1) and identifed as a favivirus by Porterfeld in 1961
(2) and was considered to be confned only to Israel and to
South Africa (3). TMEV re-emerged, or alternatively, the
extent of afected commercial turkey focks in Israel increased
during the year 2010. Te virus infection is controlled by
vaccination with a live attenuated virus (4).
TMEV belongs to the mosquito-borne cluster, clade
XI (5) and Ntaya Flavivirus Antigenic Complex VI (6).
TMEV causes a neuroparalytic disease expressed as paresis,
incoordination, dropping wings and mortality that can reach
up to 80% of the fock in commercial turkeys (7). Te frst
molecular characterization was initially described indepen-
dently by Davidson (8,9) and Kuno (5), serving thereafter for
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Israel Journal of Veterinary Medicine  Vol. 70 (2)  June 2015 Davidson, I. 4
the diagnostic assay development (10, 11). Coincidently, in
the same year, several TMEV-similar faviriruses, belonging
to the Ntaya antigenic subgroup, have re-emerged in Spain,
China, India and Malaysia, as detailed below.
Bagaza Virus (BAGV)
A BGA outbreak in wild partridges and pheasants in Cadiz,
Southern Spain was documented during late 2010 (12). Te
BAGV infection caused an increased rate of death in wild
birds, following weakness, incoordination, ataxia, weight loss
and diarrhoea. Te causative role of BAGV was demonstrated
experimentally, showing the virus’ presence in most internal
organs. However, the organs most afected were the central
nervous system and the spleen.
Tembusu Virus (TMUV)
TMUV (13,14) outbreaks in Chinese ducks emerged in
China during the year 2010, although it was already described
from China and Kuala Lumpur in 1955. Egg laying and 3-21
day-old ducklings were afected, showing retarded growth,
high fever, loss of appetite, decreased egg production and
extensive death.
Baiyangdian Virus (BYD)
Te BYD virus is a new Tembusu-related favivirus dis-
covered in China during the year 2010 (15). Te disease is
economically important due to its causing a severe drop in
egg production in ducks. Te experimental disease revealed
the virus’ afnity for the oviduct and geese ovaries.
Sitiawan Virus (SV)
Te SV virus afected Malaysian 4–6 weeks-old chicks (16),
causing leg stretching and mobility impairment, as well as
encephalitis and growth retardation. Te clinical disease
caused by both TMUV (in ducks) and SV (in chickens) was
reproduced experimentally, showing viremia with a high af-
fnity for the central nervous system at 6 days post infection.
Ntaya Virus (NTAV)
Te NTAV virus was frst discovered in Uganda in the year
1951, but has lately attracted increased interest regarding its
genomic sequencing (17). NTAV is neurotropic in wild birds,
causes haemorrhages in the brain, lungs, liver, heart, ovaries
and splenomegaly.
Usutu Virus (USUV)
USUV was frst described during the years 2001 and 2012 in
blackbirds (robins) in Germany (18, 19). Te USUV-infected
birds were asymptomatic with sudden deaths. During the
year 2009 USUV afected several immunocompromised
persons in Italy (20).
West Nile Virus (WNV)
WNV is the most renowned favivirus, representing one of
the major zoonoses, afecting wild birds, duck, horses and
humans (21). Te virus was initially described during the
year 1998 in Israel and in Romania and a year later in New
York (22). WNV causes a broad spectrum of symptoms (from
febrile rash to fatal encephalitis) and is basically a neuro-
invasive disease. Te WNV pathogenicity for birds difers,
depending on the virus strain and the avian species afected.
CHARACTERISTICS OF FLAVIVIRUS
Flaviviruses virions are spherical (about 50 ηm) in diameter,
consisting of a tightly adherent lipid envelope that may
display glycoprotein spikes, surrounding a spherical nucleo-
capsid with icosahedral symmetry (23). Te viral genome
consists of a single molecule of linear positive-stranded RNA
of about 10.5-11
Kkb, encodes for one long open reading frame that is
further processed into 10 proteins. Te mature viral proteins
are created by co- and post-translational processing and
cleavage into three structural proteins, the nucleocapsid (C),
prM, a precursor glycoprotein that is cleaved during virus
maturation to yield the trans-membranal protein (M) and the
major spike glycoprotein envelope protein, which is also the
major target for neutralizing antibodies (E). Te seven non-
structural proteins include the NS5, the RNA-dependent
RNA polymerase, NS3, with several functions, including
helicase, protease and contribution to the RNA polymerase
complex activities. NS2B and NS3 are largely responsible for
the polyprotein cleavage and the host-cell proteases which are
accountable for the remainder of this processing. Additional
NS proteins include NS1, NS2A, NS2B, NS4A and NS4B.
Structural proteins are encoded in the 5’ end of the genome,
while the non-structural proteins are encoded in the 3’.
Flavivirus replication involves the synthesis of comple-
mentary negative-sense RNA, serving as a template for
the genome-sense RNA synthesis, translating into a single
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Israel Journal of Veterinary Medicine  Vol. 70 (2)  June 2015 5 Avian Flaviviruses
polyprotein that is cleaved and processed to form the various
structural and non-structural proteins. For mosquito-trans-
mitted faviviruses, virion assembly occurs on membranes
of the endoplasmic reticulum and plasma membrane in
mosquito cells (23).
DISSEMINATION OF FLAVIVIRUSES
Members of the genus Flavivirus are subdivided on the basis
of their mode of transmission into 4 groups: (a) tick-borne vi-
ruses; (b) mosquito-borne viruses; (c) viruses with no known
arthropod vector; (d) viruses with no known animal host
(23). Te frst 2 groups are maintained in nature in alternate
cycles between arthropods and vertebrates, including mam-
mals and birds, as one or more hosts. Te mosquito-borne
faviviruses revealed 2 distinct epidemiological groups: the
neurotropic viruses, correlated with the Culex species vector
and with bird reservoirs, and the non-neurotropic viruses,
associated with haemorrhagic disease in humans, correlated
with the Aedes species and primate hosts. Many viruses of the
Culex clade cycle between mosquitoes and birds. Flaviviruses
infect mosquitoes by a viremic blood meal. Viruses penetrate
to the insect midgut, spread to other insect tissues and are
then secreted by the saliva. Some innate immune responses
and RNA interference mechanisms are potential mosquito
antiviral defence mechanisms, conferring genetic variability
in the favivirus competence to establish mosquito infection.
Co-adaptation of faviviruses and vectors infuences viral evo-
lution. Phylogenetic analyses demonstrated the correlation
between the viral molecular phylogeny and its ecological/
epidemiological characteristics (24, 25).
An essential feature of emerging pathogens is their abil-
ity to spread to new and unusual geographic ranges. In the
case of the faviviruses, the introduction of WNV into the
Americas in 1999 (22) and of the USUV into Europe in 2001
(19,20) exemplifed the phenomenon. During a retrospective
investigation of human encephalitis cases, that occurred dur-
ing the year 1996 in the Kerala state in India, Bagaza virus
was detected in mosquito pools and specifc antibodies were
identifed in human sera (26), however, no evidences exists
regarding BGAV’s zoonotic potential.
Among the avian faviviruses, viruses that have been
identifed in mosquitoes: NTAV was named by the locality
in Africa in which the carrying mosquitoes were caught.
USUV and TMEV were also demonstrated in mosquitoes
(27). TMUV was documented to be spread by wild house
sparrows, as an intermediate host which is the most widely
disseminated wild bird in China. Te efcient TMUV dis-
tribution might be attributed to the wide dissemination of
the secondary host bird that lives around poultry houses and
coops. SV was revealed in the course of a wide survey of
insects in search of animal and human faviviruses (16).
GENETIC RELATEDNESS OF
AVIAN FLAVIVIRUSES
Te genus Flavivirus, family Flaviviridae comprises over 70
viruses, most of them are serologically related and classifed
into 8 antigenic complexes (6) (Table 1). However, many
viruses have been added since the antigenic classifcation and
the extensive geographic, host and vector specifcity may still
Table 1: Flavivirus genus antigenic and phylogenic classifcation based
on a 1 kb NS5 gene fragment, according to Kuno G. et al. (1998) and
Calisher C.H. et al. (1989).
Group Virus Phylogenetic
Clade
Antigenic
Cluster
Non-Vector Cluster
Apot I Modoc
Sun Perlita, Jutiapa II Modoc
Montana bat, Dakar bat, Rio Bravo,
Carey Island, Phanom Penh bat,
Batu Cave
III Rio Bravo
Tick Borne Cluster
Gadjet Gully, Royal Farm, Pow,
Karshi, KFD, Langat, Omsk HF,
TBE-far eastern, RSSE, TBE-CE,
Negishi
IV TBE
Kadam, Tyulenly, Saumarez Reef,
Meaban
V Tyulenly
Mosquito-borne cluster
Edge Hill, Bouboni, Uganda, S.
Banzi, Jugra, Saboya, Potiskim
VI Uganda S.
Sepik YF VII
Sokuluk, Entebbe bat, Yokose VIII
Den 1-4 IX DEN
Kedougou
Zika, Spondweni X
TMEV, Bagaza, Tembusu, Ntaya,
THCA, , SLE, Rocio, Ihleus,
XI Ntaya
Naranjal, Bussuquara, Aroa, Iguape XII
Kokobera, Stratford XIII JE
Cacipore, Kontago, Kunjin, WNV,
Alfuy, Murrey Valley Encepalitis,
Usutu
XIV JE
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Israel Journal of Veterinary Medicine  Vol. 70 (2)  June 2015 Davidson, I. 6
introduce new features. Kuno et al. (5) provided a compre-
hensive phylogenetic classifcation, based on a 1 kb fragment
of the favivirus 3’ terminus of the NS5 gene (Table 1).
Accordingly, the various faviviruses diverged from a
putative ancestor into two branches, non-vector and vector-
borne virus clusters, while the vector-borne cluster subdivides
into tick-borne and mosquito-borne clusters. Within each
cluster, the phylogenetic clades correlate signifcantly with the
existing antigenic complexes. Separate species were defned
as virus classes with higher than 84% nucleotide sequence
identity among them. Kuno’s classifcation was based on the
NS5 gene, as this gene, encoding for a function linked to
virus replication, is considered to be more conserved than
the envelope gene.
THE “NEW LOOK” AT FLAVIVIRUSES
Te increased attention to avian faviviruses of veterinary im-
portance, which occurred independently in Israel and Spain,
commenced with a dramatic increase in turkey, partridges
and pheasant rate of diseases and mortality. In addition,
the 3 available genomic sequences of TMEV (2 diferent
sequences of the NS5 gene - AF098456 and AF013377 (9)
and the E gene sequence - AF372415), had a 93-95% homol-
ogy to BGAV genome. According to the Kuno statement
(5) mentioning that faviviruses with sequence homologies
higher than 84% are considered to be the same species, the
relatedness of TMEV and BGAV was suspected.
To verify the linkage between the two viruses, 3 BGAV
isolates and 4 TMEV isolates (one dated from the year 1995
and other 3 from the year 2010, as well as the vaccine strain)
were studied molecularly. By conventional and by real-time
PCR amplifcation of TMEV and of BGAV RNAs using
assays for both viruses, TMEV and BGAV were amplifed
similarly. No other favivirus, like USUV, JEV, WNV, KV and
no unrelated virus, like AIV, NDV, BFDV and MDV were
reactive (11, 28). Further, full genomes and polyprotein amino
acid sequences of all viruses were elucidated and compared
(29). A close relationship between all viruses was revealed; a
genomic homology of 92-96% existed between BGAV and
TMEV isolates, whereas the amino acid homology was much
higher. Tese results confrmed that BGAV and TMEV are
synonymous viruses, and may represent the same virus un-
der diferent names, as shown in the full phylogenetic tree
(29) and emphasized by zooming on the Ntaya clade (Fig.
1). Whether BGAV is able to cause disease in poultry, and
whether TMEV is able to cause a similar disease in wild birds
is still unknown.
In spite of the presently existing perception that TMEV
exists only in Israel and in South Africa (3) it seems unlikely
that other Mediterranean countries, with similar climatic
conditions and insects do not have TMEV/BGAV-like fa-
viviruses. Probably TMEV is not restricted to Israel, and
most probably TMEV/BGAV-like viruses are distributed
Northbound by bird migration, as their two major routes
from Africa passes through the Middle East and Spain (Fig.
2). In an attempt to trace TMEV in the wild, a survey of
Figure 1: Phylogenetic tree of the full genomes of several avian faviviruses (adapted from ref. 29)
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Israel Journal of Veterinary Medicine  Vol. 70 (2)  June 2015 7 Avian Flaviviruses
81 wild birds caught during all seasons of the last 2 years
in Israel, including diferent types of wild birds (raptors,
song and water birds), but no TMEV positive brain tissue
RNA was detected (Davidson et al., unpublished). However,
although the low statistical chance of detecting TMEV, the
possible spread of TMEV via migratory birds cannot be
excluded.
Finally, the disease emergence in these two global loca-
tions and the molecular similarities directs us towards “A
New look at Flaviviruses”, giving “food of thought” and clues
for a novel perception that additional similar viruses might
be revealed in the future.
ACKNOWLEDGEMENT
Te valuable contribution of the following colleagues from
the Veterinary Institute to the studies of TMEV, as cited
above, is warmly acknowledged - Dr. Avishai Lublin, Dr.
Shimon Perk, Mrs. Amira Al-Touri and Ms. Israel Reibshtein
from the Division of Avian Diseases, and Dr. Yevgeny
Chinick and Michael Simanov from the Division of Virology,
Kimron Veterinary Institute; Dr Nati Elkin, Biovac Ltd.,, Or
Akiva Israel is hearty acknowledged for the initial drive to
link TMEV and BGAV and Dr. Chanoch Yuval, Israel is
acknowledged for the drive to renew the TMEV study
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