Family Rhabdoviridae - Viruses And Human Disease

In this event, the sequences at the two ends of the genome

(VSNJV), and Alagoas. VSIV is the prototype virus of the

or antigenome that encompass these promoters would be

genus and has a genome size of 11,161 nt. The genome is

complementary.

neither capped nor polyadenylated, consistent with the fact

that it is minus-strand RNA.

Host Range of the (-)RNA Viruses

Synthesis of mRNAs

All seven families contain members that infect higher

The VSV nucleocapsid has about 1250 copies of N pro-

vertebrates, including humans. For five of the families, only

tein as its major structural component, leading to the con-

vertebrate hosts are known. The rhabdoviruses and bunyavi-

clusion that each N protein interacts with 9 nucleotides of

ruses, however, have a broader host range. Some are arbo-

RNA. The nucleocapsid also contains about 470 molecules

viruses that replicate in an arthropod vector as well as in a

of P and 50 copies of L. It can synthesize RNA, and P, L,

vertebrate host, and others infect only insects. In addition,

and N are all required for this activity. The organization

some genera of rhabdoviruses and bunyaviruses consist of

of the genome and the production of five mRNAs from

plant viruses. Some of these are transmitted to the plants by

it are illustrated in Fig. 4.2. There is a single polymerase

insect vectors in which the viruses also replicate.

entry site at the 3′ end of the genome, and production of

mRNAs is obligatorily sequential. Synthesis begins at the

exact 3′ end of the genome and a leader RNA of 48 nucleotides

FAMILY RHABDOVIRIDAE

is first synthesized. The leader is released and synthesis of the

The genome organization of the rhabdoviruses is the

first mRNA, that for N, is initiated. The RNA polymerase com-

simplest of the (-)RNA viruses and it is useful to begin our

plex has capping activity, and the mRNA is capped during or

coverage with this group. The genome is a single piece of

shortly after initiation. At the end of the gene for N, the tran-

minus-strand RNA 1115 kb in size. The genomes of all

scriptase reaches a conserved sequence AUACUUUUUUU,

rhabdoviruses contain five core genes, called N, P, M, G, and

where it begins to stutter and produces a poly(A) tract at the

L in that order in the genome reading 3′ to 5′, which result

3′ end of the mRNA. The polymerase complex will not termi-

in the production of five to seven proteins, five of which are

nate or stutter unless the conserved AUAC is present imme-

present in the virion. Some rhabdoviruses contain only these

diately upstream of the U7 tract, and the sequence AUACU7

five genes, but others contain one to five extra genes inserted

is therefore a consensus termination-polyadenylation signal.

in various regions of the genome. The animal rhabdoviruses

The capped and polyadenylated mRNA for N is terminated

are bullet shaped, approximately 200 nm long and 75 nm in

and released, the transcriptase skips the next two nucleotides,

diameter (Fig. 2.23), whereas some of the plant viruses are

which are referred to as the intergenic sequence, and initi-

bacilliform, being rounded at both ends. The rhabdoviruses

ates synthesis of the second mRNA, that for P, at the con-

infect mammals, birds, fish, insects, and plants, and are pres-

served gene start signal UUGUC. Following synthesis of this

ently divided into six genera. A listing of these genera and a

mRNA, the polymerase again stutters at the oligo(U) tract in

representative sample of the viruses in each genus, together

the AUACU7 signal to produce a poly(A) tract, releases the

with several characteristics of each virus, are shown in Table

capped and polyadenylated mRNA, skips the next two nucle-

4.2. Members of three genera infect mammals, namely, the

otides, and begins synthesis of the third gene, that for M. The

vesiculoviruses (type virus: vesicular stomatitis Indiana

process continues in this way through the fourth gene (the G

virus), lyssaviruses (type virus: rabies virus), and ephemero-

protein) and the fifth gene (the L protein, L for large because it

viruses (type virus: bovine ephemeral fever virus). The

comprises about 60% of the genome). In this way, five capped

novirhabdoviruses infect fish, and the cytorhabdoviruses and

and polyadenylated mRNAs are produced. In VSV, the inter-

nucleorhabdoviruses infect plants. Some or all of the mem-

genic sequence is always two nucleotides. After releasing the

bers of four genera are transmitted by arthropods (Table 4.2).

L mRNA, the polymerase complex terminates synthesis some

50 nucleotides before the 5′ end of the genome is reached.

In addition, a large number of the more than 175 currently

known rhabdoviruses have not been assigned to a genus. The

As described earlier, synthesis of the mRNAs proceeds in

animal rhabdoviruses replicate in the cytoplasm, but certain

strict sequential order and the attenuation that occurs at each

of the plant rhabdoviruses may replicate in the nucleus.

initiation step results in a gradient in the amounts of mRNAs

produced. This attenuation appears to be important for regu-

lation of the virus life cycle, so that the mRNAs for proteins

Genus Vesiculovirus

needed in most abundance are produced in most abundance.

Vesicular stomatitis virus (VSV) has been extensively

Reorganization of the genome to change the order of genes

studied and serves as a model for the replication of (-)RNA

gives rise to viable virus, but the yield of such virus during

viruses in general and rhabdoviruses in particular. Three

an infection cycle in cultured cells, and thus the fitness of the

serotypes have been recognized, Indiana (VSIV), New Jersey

virus, is reduced.

TABLE 4.2 Rhabdoviridae

Virus name

Transmission/

World

Genus/members

abbreviation

Usual host(s)

vector?

Disease

distribution

Vesiculovirus

Vesicular stomatitis

VSIV

Humans, horses,

Airborne, Insects?

Vesicles on

Americas

Indiana

ruminants, swine

tongue and lips

Chandipura Virus

CHPV

Mammals, including

Sandflies

Febrile illness

India, Asia?

humans

Piry

PIRYV

Mice, humans

Sandflies

Febrile illness

Brazil

Lyssavirus

Rabies

RABV

Humans, dogs, skunks,

Infectious saliva

Malaise, then

Worldwide except

foxes, raccoons

delirium, then

some islands, and

coma and death

Australia

ABLV,b EBLV,

Bats, humans

Infectious saliva

Like rabies

Europe, Africa,

Bat lyssaviruses

LBV

Australia

Mokola

Humans, dogs, cats,

Like rabies

Africa

shrews

Ephemerovirus

Bovine ephemeral fever

BEFV

Cattle, water buffalo

Hematophagous

Fever, anorexia

Africa, Asia,

arthropods

Australia

Adelaide River

ARV

Cattle

Berrimah

BRMV

Cattle

Novirhabdovirus

Infectious hematopoietic

IHNV

Salmonid fish

Waterborne,

Hemorrhage

Pacific Northwest of

necrosis (and other

contaminated

North America

fish viruses)

eggs

Cytorhabdovirus

Lettuce necrotic yellows

Plants

Aphids

Northern cereal mosaic

Plants

Leafhoppers

Strawberry crinkle

Plants

Aphids

Nucleorhabdovirus

Potato yellow dwarf

Plants

Leafhoppers

Maize mosaic

Plants

Leafhoppers

Sonchus yellow net

Plants

Aphids

Representative members of each genus are shown, and the first virus listed is the type species.

Virus name abbreviations: ABLV, Australian bat lyssavirus; EBLV, European bat lyssaviruses -1 and -2; LBV, Lagos bat virus.

The mRNAs for N, M, G, and L are each translated into

Replication of the Genome

a single protein. That for P is translated into three proteins.

Synthesis of viral proteins, in particular of the N protein,

The major translation product of this mRNA is P, which is

produced using an initiation codon near the 5′ end of the

allows the enzymatic activity present in the genomic nucleo-

capsid to switch from synthesis of messengers to replication

mRNA. Initiation of translation also occurs at two down-

of the genome. Replication requires producing a full-length

stream AUGs. These two downstream AUGs are in frame

antigenomic template, and the immediate encapsidation of

with one another but in a different reading frame from P. Use

the newly synthesized (+)RNA into plus-strand RNP contain-

of these alternative AUGs leads to the synthesis of short pro-

ing N, P, and L during synthesis is required. In the absence

teins of 55 and 65 amino acids (of which the shorter protein

of N for encapsidation, the system defaults to synthesis of

is a truncated version of the longer one). The functions of

mRNAs. The M protein also appears to regulate RNA synthe-

these small proteins have not been established for VSV, but

sis. In the replication mode, the polymerase complex ignores

extra products translated from the P gene of the paramyxovi-

all of the initiation, termination, and polyadenylation signals

ruses are known to interfere with host defense mechanisms,

utilized to produce mRNAs, and instead produces a perfect

as described later.

Location of intergenic sequences of VSV (a rhabdovirus), and detailed view of the M/G intergenic region

...AUAGGGAUACUUUUUUUGAUUGUCUCUAG...

Genome RNA

AACAGAGAUC...3

...UAUCCCUAUG poly(A)

mRNAS

M mRNA

G mRNA

Genomic sequences at other intergenic regions in the VSV genome

...CGAUGUAUACUUUUUUUGAUUGUCUAUAG...

...CAUCUGAUACUUUUUUUCAUUGUCUAUAG...

P/M

...UUAAAAAUACUUUUUUUGAUUGUCGUUAG...

G/L

FIGURE 4.2 (A) Schematic diagram of the VSV genome. le is the leader sequence; tr is the trailer sequence. The 5

genes N, P, M, G, and L were defined in the legend to Fig. 4.1 and are described in more detail in the text. The positions of

the conserved regulatory sequences at the gene boundaries are shown by the triangles. Each of these intergenic sequences

is composed of E (end), I (intergenic), and S (start) domains. (B) Sequences in VSV at the other three gene boundaries.

Data for this figure came from Rose and Schubert (1987).

complementary copy of the genome. The antigenomic RNA

about 1200 molecules of G, present as trimers that form

can be copied by the polymerase activity in the (+)RNP to

spikes visible in the electron microscope, and about 1800

produce more genomic RNA. This also requires that the RNA

molecules of M.

be immediately encapsidated. The new genomic RNP can be

used to amplify the replication of viral RNA or, later in infec-

Vesiculovirus Diseases

tion, can bud to produce progeny virions.

VSV causes nonfatal but economically important and

debilitating disease in cattle, pigs, and horses. The name

Maturation of Virus

of the virus comes from the vesicles that it induces on the

The G protein has a 16-residue N-terminal signal

tongue and lips. These symptoms resemble those caused by

sequence that leads to its insertion into the endoplasmic

foot-and-mouth disease virus and epidemics of VSV disease

reticulum during translation. The signal is removed by

in domestic animals result in disruptive quarantines as well

cellular signalase. The resulting 495-residue protein is

as complications in efforts for control of FMDV. Human

anchored near the C terminus by a 20-residue transmem-

infection is common in rural areas where VSV is endemic in

brane anchor, with the 29 C-terminal residues forming a

domestic animals; 2590% of farmers in such areas may have

cytoplasmic domain (i.e., it is a type 1 integral membrane

anti-VSV antibodies, showing past infection by the virus.

protein). G is glycosylated on two asparagine residues

Human infection is largely asymptomatic or associated with

and transported to the plasma membrane, where progeny

a mild febrile illness, sometimes accompanied by herpes-

viruses are formed by budding (Fig. 2.23D). The M pro-

like lesions in the mouth or on the lips or nose. Serological

tein appears to form an adaptor between the glycoprotein

surverys also show that the virus infects bats, deer, and mon-

present in the plasma membrane and the nucleocapsids

keys in endemic areas. The virus also replicates in numer-

assembled inside the cell. M also acts to repress RNA

ous arthropods and has been isolated from mosquitoes, sand

synthesis by the viral nucleocapsid. The G protein con-

flies, black flies, culicoides, houseflies, and eye gnats. The

tains the fusion activity and receptor recognition activi-

natural cycle of VSV in nature is not understood and the epi-

ties of the virus, and it is the only protein present on

demiological importance of mosquitoes or other hematopha-

the surface of the virion. The assembled virion contains

gous arthropods in transmission of the virus is not clear.

VSV is endemic in Latin America from Mexico to

Rabies Virus

northern South America where outbreaks of disease occur

Most lyssaviruses cause the disease called rabies in

every year. VSNJV accounts for the majority of the clini-

humans and other mammals. It is a uniformly fatal disease

cal cases in this region. Sporadic outbreaks occur both

of man and of other mammals, and has been known since the

north and south of this endemic area. In the United States,

twenty-third century b.c. Rabies virus is present in the saliva

sporadic outbreaks occur in the Southwest at intervals

of a rabid animal and is transmitted by its bite. Infection

of about 10 years, caused by both VSIV and VSNJV.

begins in tissues surrounding the site of the bite. Without

In the Southeast, VSNJV was endemic until the 1970s.

treatment the virus may be transmitted to the brain, where

After this, VSNJV remained endemic only on Ossabaw

replication of the virus leads to the disease called rabies. It is

Island off Georgia, where it is transmitted to feral pigs by

believed that the virus enters neurons by using acetylcholine

sand flies. In the rest of the Southeast, no clinical disease

receptors as a receptor, followed by transport up the axon

caused by VSV has been reported since 1976 and there

until it reaches the cell body. The probability that rabies will

have been only occasional findings of seropositive wild

develop following the bite of a rabid animal depends on the

animals.

location of the bite, the species doing the biting, and the virus

Chandipura virus, another member of the genus

strain. In the absence of treatment, bites on the face and head

Vesiculovirus (Table 4.2), is widespread in India, where

result in rabies in 4080% of cases, whereas bites on the legs

it infects humans and domestic animals. It is also present

result in rabies in 010% of cases. The incubation period to

in Senegal. It has been isolated from sand flies, which are

development of symptomatic rabies can vary from less than

believed to serve as vectors of the virus. Until recently it

a week to several years. Once the virus reaches the brain, it

was thought to cause no disease or only mild febrile illness

spreads from there to a variety of organs. To be transmitted, it

in humans. However, recent epidemics of encephalitis in

must spread to the salivary glands. Infection of neurons in the

children in India in 2003 and 2004 have been traced to the

brain may result in behavioral changes that cause the animal

virus, showing that it has the potential to be a significant

to become belligerent and bite other animals, so that the virus

human pathogen. In the 2003 epidemic in Andhra Pradesh,

present in salivary fluid is transmitted. In humans, the disease

for example, 183 of 329 affected children died.

may be paralytic or may result in nonspecific neurological

More than 20 other vesiculoviruses are known. As one

symptoms including anxiety, agitation, and delirium. Biting

example, Isafahan virus has been isolated from sand flies

behavior is not a consequence of rabies-induced neurological

in Iran. There is serological evidence of human infection in

disease in humans, and human-to-human transmission does

several central Asian countries but no definite evidence for

not occur. Two to 7 days after symptoms of rabies appear,

human illness caused by it.

coma and death ensue. Only three cases of humans recovering

from symptomatic rabies have been recorded.

Genus Lyssavirus

For centuries, the saliva of a rabid dog was thought to

The rhabdovirus of greatest medical interest is rabies

be the source of rabies infection, but it was only in 1804

virus, which belongs to the genus Lyssavirus. Seven geno-

that Zinke succeeded in transmitting rabies from it. In the

types or species of lyssavirus are currently recognized and

late 1800s, Pasteur adapted rabies virus to laboratory ani-

two additional genotypes have been proposed. Genotype

mals and developed the concept of protective vaccination

1 is classical rabies virus and is virtually worldwide in

against rabies. The dessicated spinal cords from rabies-

distribution. It is the only lyssavirus found in the United

infected rabbits became the first rabies vaccine. On July 6,

States where it infects a wide range of hosts, notably

1885, this vaccine was used to immunize Joseph Miester,

raccoons, wolves, skunks, and bats. Mokola virus is an

who had been bitten 14 times by a rabid dog. Because of the

African virus that is known to infect dogs and cats as

multiplicity of bites, he would almost surely have died, but

well as shrews and humans. The remaining five geno-

the Pasteur vaccine saved him. A vaccine grown in nervous

types are bat-associated lyssaviruses. Lagos bat virus and

system tissue and inactivated by phenol rather than drying

Duvenhage virus are African, there are two European bat

was the accepted rabies vaccine for decades. In the 1960s,

lyssaviruses called type 1 and type 2, and Australian bat

a safer inactivated virus vaccine derived from virus grown

lyssavirus is Australian as its name implies. Two addi-

in cultured human cells was introduced. The rabies vaccine

tional genotypes of bat viruses present in central Asia

is unique in that it is normally given after exposure to the

have been proposed.

virus, in conjunction with anti-rabies antiserum. This is pos-

The genome of rabies closely resembles that of the VSV,

sible because there is a window of time following the bite of

although very little sequence identity exists between the

a rabid animal before rabies develops, during which a pro-

genomes of the viruses belonging to the two genera. One

tective immune response can be induced. Veterinarians and

difference is the lack of a second protein encoded in the P

wildlife workers who are potentially exposed to rabid ani-

gene of lyssaviruses.

mals, as well as biologists who work with rabies virus in the

laboratory, are immunized prophylatically, but the protective

protein, using bait containing one of these viruses that is dis-

immune response can be of short duration and immunity

persed by hand or by airplane. In the eastern United States,

must be tested at regular intervals.

spread of baits has been used to slow or prevent the further

In the United States, Canada, and Western Europe, where

spread of rabies up the eastern seaboard. In Europe, baits

vaccination of domestic dogs is widely practiced, wild ani-

have been used to set up barriers to halt the spread of rabies

mals such as raccoons and skunks maintain the virus and

in foxes. The European efforts have been more successful

transmit it to humans or their domestic animals. Fig. 4.3

than those in the United States.

shows the decline in number of cases of rabies in dogs and

The perpetuation of rabies in nature is somewhat of a

humans in the United States since the 1940s, the result of

mystery because of the fact that it can be maintained only

compulsory vaccination of pet dogs. Fig. 4.3 also shows

in rabid animals who die quickly of the infection. How is

the increase in rabies in wild animals since 1940. Fig. 4.4

it that the virus manages to persist? One possibility arises

illustrates the explosive spread of rabies in raccoons on

from recent findings that rabies virus can establish a latent

the eastern seaboard in the last 20 years. The focus of this

infection in humans. Five cases have been documented in

spread in Virginia arose from the import of 3500 raccoons

which people did not develop symptoms for 7 or more years

from Florida into the Washington, D.C., area by members

after infection with the virus. In at least some of these cases,

of the cabinet of President Carter, for the purpose of rac-

progression to rabies appeared to be triggered by hormonal

coon hunting. These imported animals ignited an epidemic

changes during puberty. If the virus can establish a latent

of rabies in raccoons that has slowly spread up and down

infection in other animals that is later followed by reemer-

the Atlantic seaboard, as shown in Fig. 4.4. In other parts of

gence of the virus and its transmission to new susceptibles,

the United States, foxes and skunks are important hosts for

this could serve as a reservoir of the virus.

rabies and disease also occurs at times in wolves and coyo-

Bats may also be an important reservoir of (classical)

tes. Bats are also an important carrier of rabies. In other parts

rabies virus (bat lyssaviruses are discussed separately later).

of the world, where licensing and immunization of pets is

Rabies virus infection of bats seems to take longer to kill

not required, domestic dogs continue to be the principal vec-

the animal, during which time the virus may be transmis-

tors that transmit rabies to humans. Rabies remains a signifi-

sible through the bite of an infected bat or through aerosols

cant global health problem. More than one million people

from infected bat feces or saliva spray. However, rabies virus

annually undergo antirabies treatment following exposure to

in bats is distinguishable from rabies virus strains in other

the virus, and 50,000 people die of rabies each year.

wildlife by nucleotide sequence analysis. Thus, mixing of

Efforts to control rabies in wildlife in the United States and

bat rabies and rabies in other wildlife is infrequent. Bats can

Western Europe have met with some success. These efforts

transmit rabies to humans, and cases of human rabies trans-

involve vaccinating wildlife with attenuated rabies virus or

mitted by bats in the United States have been documented.

with recombinant vaccinia viruses that express the rabies G

In fact, in the United States in recent years, cases of human

10,000

Dogs

8000

Wildlife

6000

4000

Human Rabies

DEATHS

2000

CASES

2010

1940

1950

1960

1970

1980

1990

2000

Year

FIGURE 4.3 Rabies in domestic dogs and wild animals (right scale) versus human cases (left scale) in the United

States 19402003. Note that untreated rabies in humans is uniformly fatal. Data from Smith et al. (1995), and MMWR

Summaries of Notifiable Diseases, 1996 and 2003.

Vermont

Maine

New Hampshire

Massachusetts

New York

Rhode Island

Connecticut

Pennsylvania

New Jersey

Delaware

Ohio

West

Maryland

Virginia

Kentucky

North Carolina

Tennessee

South

Carolina

1977-1979

1980-1984

Georgia

1985-1989

Alabama

1990-1993

Florida

1994-1998

1999-2003

No raccoon rabies

detected

FIGURE 4.4 Spread of raccoon rabies over 3- to 5-year increments in the states of the Atlantic seaboard. Over 25 years

the virus has spread from a small focal area in northern Virginia to encompass much of the entire region from southern

Maine to Florida. From Morbidity and Mortality Weekly Report (MMWR) (1997) Vol. 45, p. 1119, updated with data from

CDC found on www.rabavert.com/caserc.html.

rabies resulting from infection with bat-associated rabies

There are two major types of bats. Bats belonging to the

virus have been more numerous than cases resulting from

suborder Megachiroptera, of which 40 genera are recognized,

infection by bites of other rabid wildlife. In many cases of

are large and feed on fruit and nectar in flowers. Members

bat-associated rabies, the mechanism by which the virus was

belonging to the genus Pteropus are often called flying foxes

transmitted to the human is not known, because no exposure

and are found from Australia across India to Madagascar.

to bats, rabid or otherwise, could be shown.

There are four species of flying foxes in Australia. Bats

belonging to the suborder Microchiroptera are smaller, feed

on insects, and have developed echolocation to find their

Bat Lyssaviruses

prey in the dark. Both types of bats carry ABLV in Australia,

Australia was long believed to be completely free of

and of the two cases of human infection that have resulted,

rabies. However, it has recently been found that many

one was from a flying fox and the second was from an insec-

Australian bats carry a virus known as Australian bat lys-

tivorous bat. The strains of virus in the two types of bats

savirus (ABLV). Two cases of fatal human rabies that were

are distinguishable, differing by about 20% in nucleotide

caused by infection with this bat virus have occurred in the

sequence.

last few years. In one case, a woman caring for injured bats

Two different European bat lyssaviruses exist. Four

was bitten by a bat in her care. In the second incident, a

human deaths resulting from infection by these viruses have

woman was bitten while trying to remove a bat that had

occurred, and there is concern that more cases might occur.

landed on a child. No rabies has been found in other animals,

Mokola virus has also infected humans in Africa.

presumably because there is no efficient mechanism for

transmission of the virus among other mammals present in

Other Genera of Rhabdoviruses

the continent. However, the disease could potentially spread

to dogs and cats that have been introduced into Australia

Bovine ephemeral fever virus, genus Ephemerovirus, is

over the years.

an arbovirus that causes economically important disease in

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