img
domestic cattle and water buffalo in tropical areas of the Old
that still other genes are hidden within some of these large
World. This virus, as well as other members of the genus, are
genomes. For example, the SH gene, encoding a very small
not known to be human disease agents. The genome encodes
protein, was discovered only recently.
five additional genes located between G and L. One of these
The N or NP (= N in rhabdoviruses), P, M, and L proteins
encodes an additional glycoprotein whose significance is
serve the same functions as their counterparts in rhabdovi-
unknown. The other four genes encode five small proteins
ruses. G of rhabdoviruses is replaced by two glycoproteins
of unknown function.
in paramyxoviruses, one called F and the other H or HN or
The novirhabdoviruses infect salmon and other fish and
G, depending on the virus. The order of genes in the para-
are responsible for economic losses in fish farming opera-
myxoviruses is the same as in the rhabdoviruses, and the
tions. One additional gene is present in infectious hema-
genome of the ancestral paramyxoviruses could have arisen
topoietic necrosis virus, located between G and L. The
from that of a rhabdovirus by insertion of extra genes (or
nucleorhabdoviruses and cytorhabdoviruses are plant viruses
vice versa by deletion of genes). Of interest is the fact that
that are transmitted by arthropods. They replicate in both
the rhabdovirus N protein binds nine nucleotides whereas
the arthropod vectors as well as in plants and are the plant
the paramyxovirus N protein binds six nucleotides, and
equivalent of arboviruses. Two (in maize fine streak virus, a
paramyxoviral RNAs, where studied, contain a number of
nucleorhabdovirus) or four (in northern cereal mosaic virus,
nucleotides divisible by six.
a cytorhabdovirus) additional genes are positioned between
Virus replication occurs in the cytoplasm. Like the
P and M. There are in addition many plant rhabdoviruses
rhabdoviruses, paramyxovirus mRNAs are transcribed
that have not been assigned to genus.
sequentially beginning at the 3 end of the genome and the
mechanisms to produce these mRNAs are similar to those
employed by rhabdoviruses. A leader is first transcribed,
FAMILY PARAMYXOVIRIDAE
poly(A) tracts are added by stuttering at oligo(U) stretches at
the end of each gene, intergenic nucleotides are skipped by
The family Paramyxoviridae has seven genera, listed in
the polymerase during synthesis of mRNAs, and attenuation
Table 4.3 together with representative viruses in each genus.
of mRNA synthesis occurs at each junction. The intergenic
The relationships among the genera are illustrated in the
nucleotides are variable among paramyxoviruses, however.
tree shown in Fig. 4.5. Each genus represents a distinct line-
They are GAA or GGG for some viruses, but are variable in
age. Furthermore, Respirovirus, Morbillivirus, Henipavirus,
sequence and in length, from 1 to 60 nucleotides, for others.
and Rubulavirus are more closely related to one another
The mechanisms by which the virus switches from synthe-
than to Pneumovirus and Metapneumovirus, and the fam-
sis of mRNAs to replication of the genome are the same as
ily is divided into two subfamilies, Paramyxovirinae and
those used by the rhabdoviruses.
Pneumovirinae. Many of the viruses belonging to this fam-
ily are very important human pathogens. Some, such as mea-
The Viral Glycoproteins
sles virus and mumps virus, have been known for a long
time--the infectious diseases caused by these viruses were
Paramyxovirus virions are 150­350 nm in diameter and
known to the ancients. At the other extreme, Hendra virus,
contain a helical nucleocapsid that is 8­12 nm in diameter.
first described as an "equine morbillivirus of Australia," and
Virions are usually round but pleomorphic (Fig. 2.22C), and
the related Nipah virus of Southeast Asia have been known
filamentous forms are also produced by some viruses that are
for less than a decade. These two new viruses have been
more common in clinical isolates (Fig. 2.25E). Virions are
classified into a new genus, Henipavirus.
produced by budding from the plasma membrane (Figs. 2.25E
and F). The virion size differs even within a single species and
the composition of the virion is not as well defined as for some
Replication of the Paramyxoviridae
enveloped viruses. There are two glycoproteins on the surface.
The genome organizations of five viruses representing
One is a fusion protein that is required for the fusion of the viral
five genera of the paramyxoviruses are shown in Fig. 4.6.
membrane with the cell plasma membrane. Paramyxoviruses
The paramyxovirus genome is larger than that of the rhab-
fuse with the plasma membrane, not with endosomal mem-
doviruses, 15­20 kb, and encodes more proteins, 8­11 or
branes, and fusion does not require exposure to low pH. The
more. A core of six genes is present in paramyxoviruses,
fusion protein is produced as a precursor called F0. When first
N, P, M, F, H, L (different names are used for some of the
synthesized, F0 has an N-terminal signal sequence that results
genes as shown in the figure). The P gene uses more than
in its insertion into the endoplasmic reticulum during transla-
one reading frame to encode multiple proteins in most of
tion. The signal sequence is removed by signal peptidase and
these viruses. Rubulaviruses possess a seventh gene, encod-
the resulting type 1 integral membrane protein is anchored
ing a protein called SH, and pneumoviruses possess an even
by a membrane-spanning region near the C terminus. F0 is
larger constellation of genes, 10 in number. It is possible
cleaved either by cellular furin (many paramyxoviruses)
img
TABLE 4.3 Paramyxoviridae
Virus name
World
a
Genus/members
abbreviation
Usual host(s)
Transmission
Disease
distribution
Paramyxovirinae
Respirovirus
Human parainfluenza 1,3
HPIV-1,3
Humans
Airborne
Respiratory disease
Worldwide
Bovine parainfluenza 3
BPIV-3
Cattle, sheep
Airborne
Respiratory disease
Worldwide
Sendai
SeV
Mice
Airborne
Respiratory disease
Worldwide
Rubulavirus
Mumps
MuV
Humans
Airborne
Parotitis, orchitis,
Worldwide
meningitis
Human parainfluenza 2, 4a,4b HPIV-2,4
Humans
Airborne
Respiratory disease
Worldwide
Simian virus 5
SV-5
Monkeys, canines
Airborne
Respiratory disease
Worldwide
Menangle
?
Bats/swine
???
Reproductive
Australia
abnormalities
Morbillivirus
Fever, rash, SSPEb,
Worldwide
Measles
MeV
Humans, monkeys
Airborne
immune suppression
Rinderpest
RPV
Cattle, swine
Airborne
Gastroenteritis
Worldwide
Distemper
CDV, PDV
Dogs, marine
Airborne
Immune suppression,
Worldwide
mammals
gastroenteritis,
CNS disease
Henipavirus
Hendra (equine morbillivirus) HeV
Humans, equines,
Body fluids?
Respiratory disease,
Australia
Pteropus fruit bats
encephalitis
Nipah
NiV
Humans, swine,
Body fluids?
Respiratory disease,
Malaysia,
cats, dogs
encephalitis
Singapore
Avulavirus
Newcastle disease, avian
NDV
Gallinaceous birds
Airborne
Respiratory distress,
Worldwide
paramyxoviruses 2­9
diarrhea
Pneumovirinae
Pneumovirus
Human respiratory syncytial
HRSV
Humans
Airborne
Respiratory disease
Worldwide
Bovine respiratory syncytial
BRSV
Cattle
Airborne
Respiratory disease
Worldwide
Pneumonia virus of mice
PVM
Mice
Airborne
Respiratory disease
Worldwide
Metapneumovirus
Turkey rhinotracheitis
TRTV
Turkeys
Airborne
Respiratory disease
Worldwide
a
Representative members of each genus are shown, and the first virus listed is the type species.
b
Abbreviations: SSPE, subacute sclerosing panencephalitis; CNS, central nervous system; CDV, canine distemper virus; PDV, phocine distemper virus.
or cathepsin L (henipaviruses) within the cell or by other
(which recognizes the sequence RXRR or RXKR) or cathep-
cellular enzymes after release of the virion from the cell,
sin L are able to spread systemically and in general cause
depending on its sequence. Cleavage is required for the
serious disease. In contrast, viruses that require cleavage of
virus to be infectious and the cleavage products, F1 (the N-
F0 by proteases after the release of (noninfectious) virions
terminal part of the precursor) and F2 (the C-terminal part
from the cell, usually at a single basic residue by trypsin-like
which is anchored in the membrane), remain covalently
enzymes such as Clara or miniplasmin that are limited in
linked through a disulfide bond. The fusion domain con-
their distribution in the animal, cannot spread systemically
sists of the N-terminal 20 amino acids of F2, but this domain
and are usually restricted to the respiratory tract. F oligomer-
izes to form trimers that are visible as spikes on the surface
is not fusogenic until cleavage of F0 has occurred. Those
of the virion.
strains whose F0 can be cleaved intracellularly by furin
img
HPIV-1
Respirovirus
SeV
HPIV-3
CDV
PDV
RPV
Morbillivirus
MeV
PPRV
Paramyxovirinae
DMV
Hendra
Henipavirus
Nipah
HPIV-4b
HPIV-4a
Rubulavirus
MuV
SV-5
HPIV-2
Avulavirus
NDV
TRTV
Metapneumovirus
Pneumovirinae
HRSV
Pneumovirus
100 nt substitutions
Species
Genus
Subfamily
FIGURE 4.5
Phylogenetic tree of the Paramyxoviridae derived from the nucleotide sequences of the N ORF. Most
of the virus abbreviations are found in Table 4.3. CDV, canine distemper; PDV, phocine distemper; PRRV, peste-des-
petits-ruminants; DMV, dolphin morbillivirus. Notice that the closest relative of measles (MeV, boxed), a human virus, is
rinderpest (RPV, boxed), a virus of cattle and pigs. Adapted from Chua et al. (2000).
RESPIROVIRUS
114
110
125
157
257
46
41
HPIV-3
N
P/C/D
M
F
HN
L
15462 nt
515
603
353
539
572
2258
RUBULAVIRUS
184 SH
133
65
115
256
152
169
SV-5
M
N
V/P
HN
L
F
15246 nt
510
392
377
529
44
565
2255
MORBILLIVIRUS
108
121
106
1003
160
109
109
MeV
P/C/V/W
N
M
F
H
L
15894 nt
525
507
335
553
617
2183
HENIPAVIRUS
672
112
676
572
475
654
100
HeV
P/C/V/W
N
M
F
G
L
18234 nt
707
352
546
604
2244
532
PNEUMOVIRUS
269 SH 189
189
227
65
216
98
107
139
32
76
HRSV
G
FM2
N
P
M
L
M2
NS1
NS2
15225 nt
139 124
391
241
256
65
299
574
195/90
2166
Genome
(kb)  0
2
4
6
8
10
16
18
FIGURE 4.6
Genome organizations of the five genera of the Paramyxoviridae that infect mammals. The genome is
shown 3to 5for the minus-strand RNA. For the top four genera, each gene begins with the vertical pink bar marking
the intergenic sequence. The untranscribed intergenic sequences of respiroviruses, morbilliviruses, and henipaviruses are
3 nt in length. Those of rubulaviruses and pneumoviruses vary in length from 1 to more than 60 nucleotides. The boxes
are the ORFs encoding the nucleocapsid (N), the P (V, C, W, D) complex, the matrix protein (M), the fusion protein (F),
the glycoprotein (G, HN, or H), and the polymerase (L). Numbers above the arrows are the total number of nucleotides
between the ORFs; numbers below the boxes are the number of amino acids in the protein. HPIV-3, human parainfluenza
virus 3; SV5, simian virus 5; MeV, measles virus; HeV, Hendra virus; and HRSV, human respiratory syncytial virus.
The second glycoprotein is called the hemagglutinin-neu-
or P/C/V gene, is remarkable, as illustrated in Fig. 4.7. The
raminidase (HN), the hemagglutinin (H), or simply G (for
P gene, or its equivalent, of most (-)RNA viruses is used
glycoprotein), depending on the virus. This protein is a type
to make more than one protein, as was described earlier for
2 integral membrane protein. The signal sequence at the
the vesiculoviruses and as will be described later for other
N terminus is not removed but instead serves as the trans-
viruses, but the translation strategies used by some para-
membrane anchor for the protein, so that it has its N termi-
myxoviruses result in maximal use of the potential informa-
nus inside and its C terminus outside. This protein contains
tion contained within this gene. In some paramyxoviruses,
the receptor-binding activity of the virus.
alternative AUG start codons are used to produce two differ-
Many paramyxoviruses belonging to the genera Respirovirus
ent proteins translated from different reading frames, simi-
and Rubulavirus use sialic acid (N-acetylneuraminic acid)
lar to what occurs in the vesiculoviruses. A second strategy
bound to protein or lipids as a receptor. Because this receptor
used by paramyxoviruses is to add nontemplated nucleotides
is also present on red blood cells, these viruses can cause red
to the mRNA during synthesis in order to shift the reading
blood cells to clump or agglutinate, a process called hemagglu-
frame downstream of the added nucleotides. The ultimate
tination (heme = the red compound in red blood cells that binds
use of the paramyxovirus P gene occurs in some viruses in
oxygen). In paramyxoviruses that use sialic acid as a recep-
which all three reading frames are translated by using one or
tor, this second glycoprotein is also a neuraminidase, in which
both of these strategies to produce four or more proteins.
case it is called HN. Neuraminidase removes sialic acid from
In respiroviruses, morbilliviruses, and henipaviruses,
potential receptors and from virus glycoproteins. By removing
translation of P mRNA can start at one of two different
sialic acid from the virus glycoproteins and from the cell sur-
AUGs that are in different reading frames. One of the two
face, released virus is prevented from aggregating with itself or
proteins produced is called C and the other P (Fig. 4.7). In
sticking to infected cells. It also increases the probability that
addition, during transcription of P mRNA in most members
the virus will successfully initiate infection of a suitable ani-
of the Paramyxovirinae, nontemplated G residues are added
mal. Mucus, which lines the respiratory tract where the viruses
at a specific site in the gene. In measles or Sendai viruses,
begins infection, contains sialic acid and might otherwise bind
addition of one G shifts the reading frame after this point
virus, preventing its entry into cells, if the virus could not
to produce a new protein called V, which is rich in cysteine
release from mucous by destroying these receptors.
residues. Thus P and V share their N-terminal sequence but
Other receptors used by paramyxoviruses include, among
diverge after the site where the extra G is added. In the case
others, CD46 (measles virus), Ephrin B2 (henipaviruses),
of parainfluenza virus 3, addition of two G's leads to mRNA
and glycosaminoglycans (respiratory syncytial virus). If the
translated into a protein called D. Another respirovirus,
receptor used by the virus is found on red blood cells, the
HPIV-1, lacks editing in the P gene (Fig. 4.7). In the rubu-
viruses will hemagglutinate, but if the receptor is not sialic
laviruses, the V protein is translated from the unmodified
acid, the virus will not contain a neuraminidase. In this case,
transcript, and production of mRNA for P requires addition
the second glycoprotein is called H. If the viruses are not
of two nontemplated G residues. In mumps virus, addition of
known to hemagglutinate, the second glycoprotein is simply
4 G residues also occurs to produce a third protein.
called G, for glycoprotein. In any event, this second glyco-
During translation of these P mRNAs, the situation
protein of paramyxoviruses, best studied in the case of the
becomes even more complicated. In some viruses, multiple
HN of some paramyxoviruses, oligomerizes to form tetra-
in-frame start codons are used to initiate translation of C.
meric spikes on the surface of the virion.
Thus, different forms of C are produced that are variously
Some paramyxoviruses belonging to the genera Rubu-
truncated at their N terminus. For example, Sendai virus
expresses four C proteins, called C˘, C, Y1, and Y2, of
lavirus and Pneumovirus encode a third integral membrane
which C˘ starts at an ACG codon. The many different pro-
protein. This small (44­64 residues) protein is called SH or
1A and is glycosylated in the pneumovirus respiratory syn-
tein products produced from the P gene have not been fully
cytial virus but not in the rubulaviruses SV5 and mumps. In
characterized, and perhaps not yet fully enumerated, and the
the rubulaviruses the protein is a type 1 integral membrane
various functions of this wealth of proteins are only partially
protein whose gene is positioned between F and H (or HN).
unraveled.
In SV5 and, probably, in mumps virus also, the protein inter-
Addition of the nontemplated G residues is thought to
feres with the TNF-α mediated apoptosis pathway. Mutants
involve a mechanism similar to the stuttering that produces
lacking this protein will replicate in cell culture but cause
a poly(A) tract opposite a string of U's in the template. The
extensive apoptosis, and are attenuated in animals.
nontemplated G's are always added at a specific, unique
place in the genome characterized by a string of C's. There
must be some signal within the genome that is recognized by
The P Gene
the viral polymerase for the addition of the extra G's, similar
Expression of the P gene of paramyxoviruses belonging
to the case for the addition of the poly(A) tract at the end of
to the subfamily Paramyxovirinae, sometimes called the P/V
mRNAs.
img
RESPIROVIRUS
HPIV- 1
C protein
P protein
SENDAI
C protein
P protein
+ 1G
V protein
* **** *
HPIV- 3
C protein
P protein
+ 2G
D protein
RUBULAVIRUS
HPIV-2, HPIV-4, SV-5
* **** *
V protein
+ 2G
P protein
MUMPS
* **** *
V protein
+ 2G
P protein
+ 4G
I protein
MORBILLIVIRUS
MEASLES
C protein
P protein
+ 1G
V protein
* **** *
HENIPAVIRUS
NIPAH
C protein
P protein
+ 1G
V protein
+ 2 ***
*G
W protein
* **** * Cysteine-rich domain
ORF1
ORF2
ORF3
FIGURE 4.7  Translation strategy of the P gene of paramyxoviruses. In most paramyxoviruses, nontemplated
nucleotides are inserted during transcription of P to shift the translation frame. Alternative translation start codons are
also used. The result is the production of up to four proteins from this one gene. Adapted from Strauss and Strauss (1991)
and Chua et al. (2000).
An important function of the V and C proteins, perhaps
production is double-strand RNA (dsRNA), and there are
the primary function, is to block the action of the hosts inter-
at least two cellular sensors that detect dsRNA and induce
feron (IFN) system. Such an activity is called a luxury func-
the production of IFN (described in more detail in Chapter
tion because it is not needed for virus replication in cultured
10). Intracellular dsRNA can be sensed by a helicase called
cells but is needed for a successful infection of an animal.
RIG-1. Through a complicated pathway involving cas-
Production of IFN is the first line of defense of birds and
pase-recruitment domains (CARD), two transcription fac-
tors, IRF-3 and NFκB, are activated and transported to the
mammals against virus infection and the system is described
in detail in Chapter 10. The importance of IFN in controlling
nucleus. These form a complex that leads to the transcrip-
tion of the mRNA for IFN-β. An overlapping pathway can
viral infection is shown by the fact that most if not all viruses
interfere with its action in some way. In paramyxoviruses,
start from extracellular dsRNA, which is bound by a cellu-
the V and C proteins act in different ways to block IFN pro-
lar receptor called Toll-like receptor 3. The resulting signal
duction or its activity once induced. A potent inducer of IFN
cascade results in the production of the same two activated
transcription factors. The V proteins of several paramyxovi-
are common). Thus, immunity is incomplete and the viruses
ruses interfere with either activation pathway, preventing the
continue to reinfect older children and adults. However, sub-
induction of IFN. In addition, the W protein of Nipah virus
sequent infections are normally less severe and there is a
blocks the activity of IRF-3 in the nucleus. The cysteine-rich
reduction in the incidence of lower respiratory tract disease
C-terminal domains of the V proteins are highly conserved
(which is more serious than infection of the upper respira-
and presumably work in the same way in this pathway.
tory tract). The viruses, as is common for respiratory tract
The V proteins, and in some cases the P proteins, also block
infections, are spread by respiratory droplets.
the activity of IFN-β once it is produced. IFN-β is exported
Attempts to develop vaccines against the HPIVs have
from the cell where it can be bound by Type I IFN receptors
not met with success. Because of incomplete immunity pro-
at the surface of the same cell or other cells. Once IFN-β is
duced by natural infections, the primary purpose of a vac-
bound, the receptor, which consists of two different subunits,
cine would be to decrease the severity of natural infection
heterodimerizes and associated adaptor proteins phospho-
by the virus. Even so, results to date have been disappoint-
rylate one another and phosphorylate transcription factors
ing. Inactivated virus vaccines developed for HPIV-1 and
called STAT1 and STAT2. Once phosphorylated, the STATs
-3, as well as for HPIV-2, a rubulavirus, were antigenic but
heterodimerize and are transported to the nucleus where they
failed to induce resistance to the viruses. This could have
form part of a transcription complex that transcribes mRNA
resulted from failure to develop IgA following a parenterally
from hundreds of IFN-responsive genes and the products of
administered vaccine (Chapter 10), and attempts to develop
these genes establish an antiviral state. The V protein and
effective vaccines are continuing.
P protein of Nipah virus cause the STATs to aggregate into
large, inactive complexes. The V proteins of several other
Genus Rubulavirus
paramyxoviruses cause STAT1 or STAT2 to be degraded by
proteasomes. The W proteins of Nipah virus also blocks the
Mumps Virus
activity of the STATs in the nucleus by causing the proteins
to aggregate. The net result of these activities is that the genes
The genus Rubulavirus gets its name from an old name
responsive to activation by IFN-β are not transcribed and IFN
for mumps, which is the disease produced in humans by
activity is aborted (see also Chapter 10).
mumps virus. The only natural hosts for mumps virus are
The V proteins are also involved in the regulation of RNA
humans and the virus is transmitted from person to person
synthesis after infection. Where studied, they downregulate
by contact. The disease has been known (at least) from the
the production of viral RNA.
fifth century b.c. The incubation period, that is, the period
of time between infection by the virus and the development
of symptoms, is about 18 days. During the last 7 days of
Genus Respirovirus
the incubation period, a person sheds virus and is capable
The genus Respirovirus contains several parainfluenza
of infecting others. Infection of children is usually not seri-
viruses (abbreviated PIVs) and Sendai virus (from Sendai,
ous, but mumps virus infection can cause serious illness,
Japan, where it was isolated; also called mouse PIV-1)
particularly in adults. Infection begins in the upper respi-
(Table 4.3). The two human respiroviruses, HPIV-1 and
ratory tract but becomes systemic with the virus infecting
HPIV-3, cause a respiratory illness similar to that caused by
many organs, where it replicates in epithelial cells. It is best
influenza virus and utilize sialic acid as a receptor, as does
known for infection of the parotid salivary glands leading to
influenza. They were once grouped with influenza virus as
painful swelling of these glands. More serious disease can
myxoviruses (myxo from mucus because the viruses attach
result from the replication of the virus in other organs, how-
to mucus, which contains sialic acid). When they were
ever. The central nervous system (CNS) is a common target
separated from influenza virus into a distinct family, they
for the virus and 0.5­2.3% cases of mumps encephalitis are
were called parainfluenza viruses and the family was named
fatal. Infection of the pancreas can occur, and it has been
Paramyxoviridae.
suggested that mumps may be associated with sudden onset
The respiratory tract infections caused by HPIV-1 and
insulin-dependent diabetes. The heart is sometimes infected,
HPIV-3 may be limited to the upper respiratory tract, caus-
resulting in myocarditis. Infection of the testes in adult males
ing colds, or may also involve the lower respiratory tract,
can lead to orchitis and, in rare cases, to sterility. Infection of
causing bronchopneumonia, bronchiolitis, or bronchitis.
the fetus can result in spontaneous abortion.
These viruses are widespread around the world and are an
At one time, mumps was one of the common childhood
important cause of lower respiratory tract disease in young
diseases that was contracted by almost everyone. It is now
children. Serological studies have shown that most children
controlled in developed countries by an effective attenuated
are infected by HPIV-3 by 2­4 years of age, and that the
virus vaccine that was selected by passage of the virus in
incidence of infection can be as high as 67 out of 100 chil-
embryonated eggs. This mumps vaccine is given as part of
dren per year during the first 2 years of life (i.e., reinfections
the MMR (measles­mumps­rubella) combination vaccine.
img
The dramatic decline in cases of mumps in the United
The avian viruses include nine serologically distinct
States after introduction of this vaccine is shown in Fig. 4.8.
paramyxoviruses. These viruses form a distinct lineage,
Because mumps is exclusively a human virus that induces
but clearly group with the rubulaviruses (Fig. 4.5). APMV-
effective immunity following infection, and infection of
1 is also known as Newcastle disease virus (NDV), which
an individual requires direct contact with a person actively
causes a highly contagious and fatal disease of birds. NDV
shedding the virus, the virus requires a population of at least
has serious economic consequences because it infects
200,000 people to sustain it. Such a population density was
chickens, among other avian hosts. When epidemics break
first attained 4000 or 5000 years ago, before which mumps
out, and they do with some regularity, many birds die,
could not have existed, at least in its current form.
causing economic losses. Quarantines are placed on the
movement of birds during epidemics in an effort to curtail
the spread of the virus, which has further economic con-
Other Rubulaviruses
sequences.
Other human rubulaviruses include HPIV-2 and HPIV-4.
Menangle virus is a newly described virus that emerged
They are named human parainfluenza viruses because the
in Australia in 1997 as the cause of severe reproductive dis-
disease they cause is similar to that caused by HPIV-1 and
ease in pigs. Menangle virus is a bat virus that was present
HPIV-3. However, they are genetically related to the rubu-
in flying foxes that formed a large colony near the pig farm
laviruses rather than to the respiroviruses (Fig. 4.5). Other
where the virus emerged. How the virus was transmitted
members of the rubulavirus genus infect many mammals
to pigs is not known with certainty. Two farm workers
and birds. One of the most intensively studied rubulaviruses
appeared to have been infected during the outbreak and suf-
(studied as a model system for replication of members of the
fered influenza-like symptoms. Menangle is an example of
family) has been SV-5 (simian virus 5). During the develop-
emerging viral diseases, a topic covered in more detail in
ment of the polio vaccine, rhesus monkey kidney cells were
Chapter 8.
used for replication of poliovirus in culture, and these cul-
tures were often contaminated with monkey viruses. These
Genus Morbillivirus
simian viruses (SVs) were simply numbered as they were
isolated, and any particular SV may be totally unrelated to
The genus Morbillivirus contains measles virus as well
any other. Two of the most widely studied are SV-5 and SV-
as a number of nonhuman pathogens that include rinderpest
40, which are not related to one another: SV-5 is an RNA-
virus, which infects cattle and pigs, and distemper viruses
containing paramyxovirus and SV-40 is a DNA-containing
of dogs, dolphins, and porpoises. The relationships among
polyomavirus (Chapter 7).
these viruses were illustrated in Fig. 4.5.
Mumps vaccine
90
licensed in 1967
80
2
70
1
60
0
50
1992
1996
2000
2004
Year
40
30
20
10
0
1968
1972
1976
1980
1984
1988
1992
1996
2000
2004
Year
FIGURE 4.8
Incidence of mumps (cases per 100,000 population) in the United States. The minor resurgence of
mumps cases in the late 1980s is thought to be due to a pool of susceptible teenagers and young adults who were not
aggressively immunized during the first decade after the introduction of the vaccine. In 2003 there were a total of 231
cases of mumps in the United States, the lowest number ever reported for one year (< 0.08 cases per 100,000). The last
deaths in the United States from mumps occurred in 2000. However, in 2006 there was a major outbreak of mumps in the
Midwest, resulting in 5783 cases. From MMWR, Summary of Notifiable Diseases-1996, Vol. 45, p. 45; the comparable
Summaries for 2001 and 2003; and MMWR (2006) Vol. 55, p. 1152.
Measles
epidemics do not last as long as when the population is dis-
persed over a larger area, such as in Iceland.
Measles virus causes serious illness in man. Infection
The study of measles epidemics on islands first demon-
begins in the upper respiratory tract but becomes systemic, and
strated that lifelong immunity arises following infection by
many organs become infected. Lymphoid organs and tissues
measles. After an epidemic of measles in the Faeroe Islands
are prominent sites of viral replication, and one consequence
in 1781, the islands were free of measles until the virus was
of virus infection is immune suppression that lasts for some
again introduced in 1846 by a Danish visitor. In the 1846
weeks, apparently due to suppression of T-cell responses.
epidemic, 77% of the population of the islands contracted
Immune suppression can result in secondary infections that may
measles, but no one over 65 years of age came down with
be serious, even life threatening, and interference with immune
the disease.
function is a major cause of measles mortality. Measles also
The requirement for a minimum sized population to
has uncommon neurological complications, including enceph-
maintain the virus means that even though measles virus is
alomyelitis and subacute sclerosing panencephalitis (SSPE). In
extraordinarily infectious, the virus could not have existed
SSPE, the virus sets up a persistent but modified infection in
until perhaps 5000 years ago when human population den-
the brain in which M protein is produced in only low amounts;
sity became sufficient to support it. At about this time, large
downregulation of production of M protein appears to be nec-
population centers arose in the Fertile Crescent, a region of
essary to establish the disease syndrome. Symptoms of SSPE
the Middle East encompassing parts of modern Iraq, Syria,
appear several years after measles infection, and the disease
Jordan, Israel, Lebanon, and Turkey, which included the
progresses slowly but inexorably. Serious complications caused
upper Tigris and Euphrates rivers and whose climate was
by viral infection of other organs can also occur.
conducive to primitive agriculture. These population centers
were associated with the cultivation of food plants and the
domestication of animals, including bovines. Measles virus
Natural History of Measles Virus
is most closely related to rinderpest virus (Fig. 4.5), which
Like mumps, measles is a disease of civilization. The virus
infects cattle and swine. An obvious hypothesis is that the
is a human virus. Although subhuman primates can be infected
close contact between humans and their domesticated ani-
by the virus and suffer the same disease as humans, humans
mals allowed rinderpest virus, or perhaps another virus of
are the only reservoir of the virus in nature. Infection requires
domestic animals, to jump to humans and evolve to become
direct contact with an infected person and recovery from
specific for humans. Subsequent coexistence of the virus
infection results in solid lifelong immunity to the virus. Thus,
with its human host led to the present situation where infec-
a minimum size population is required to maintain the virus,
tion results in significant but relatively low morbidity and
in which the continuing birth of new susceptibles occurs at a
mortality.
rate sufficient to maintain continuous virus infection within
the community. The requirement for a minimum sized human
Introduction of Measles into the Americas
population to sustain the virus is illustrated in Fig. 4.9. In this
and Island Populations
figure, data from 1949­1964 (before tourism became as popu-
lar as it is today) are plotted that show the duration of mea-
Epidemics of measles were undoubtedly widespread
sles epidemics on various islands. In Fig. 4.9A, we see that
in the Old World following the appearance of measles,
an island must have a population sufficient to produce about
although it is difficult now to ascertain the causes of epi-
16,000 surviving newborns a year (population about 500,000)
demics that occurred thousands of years ago. However, it
in order to maintain the virus continuously in the population.
is clear that measles was widespread in Europe at the time
If the population is smaller, the epidemic burns itself out when
the Europeans began their explorations of the Americas
all susceptibles have been infected. The island is then free of
and of the many isolated island communities around the
measles until sufficient new susceptibles have been born and
world, and Europeans carried measles with them as they
measles is once again introduced into the island from outside.
traveled. Introduction of measles virus into virgin popula-
The smaller the population, the longer this takes. Note that
tions resulted in very high mortality. Mortality was 26%
Guam and Bermuda, with their heavy tourist influx, had mea-
in Fiji islanders when measles was introduced in 1875,
sles present more than expected from the curve because the
for example. It has been estimated that 56 million peo-
virus is introduced more often, that is, the island population is
ple in the Americas died of Old World diseases follow-
not truly isolated. Figure 4.9B illustrates that the more densely
ing European exploration of the New World, and measles
packed the population, the more readily the virus spreads and
and smallpox (Chapter 7) were significant contributors to
therefore the sooner the epidemic burns itself out. The islands
these deaths. The introduction of measles and smallpox
shown in this panel all have about the same population, but
by the Spaniards facilitated the conquest of the Americas
when the population is compressed into a smaller area, such
by them, and the subsequent depopulation of Central and
as in Tonga, person-to-person spread is more efficient and
South America allowed the Spaniards to remain dominant.
img
100
Guam
80
60
Bermuda
40
20
0
4
8
12
16
New Susceptibles in Thousands per Year
Iceland
20
15
New Hebrides
New Caledonia
10
Solomon Islands
Western Samoa
French Polynesia
5
Tonga
0
0
1
2
3
4
5
6
7
Mean Distance Between New Susceptibles (Kilometers)
FIGURE 4.9  Effect of population size and density on the epidemiology of measles. Upper panel: percent of months
with measles (true endemicity = 100%) in island populations as a function of number of new susceptibles per year.
Measles periodically fades out in isolated populations of less that 500,000 (= approximately 15,000 new susceptibles
per year). Each dot represents a different island population. Note that Guam (with a transient military population) and
Bermuda (with a steady influx of tourists) do not fall on the curve, as they are not truly isolated populations. Vaccination
for measles can reduce the number of new susceptibles, even in large urban populations, below the number needed to
sustain transmission. Data from Black (1966). Lower panel: relation between the average duration of measles epidemics
and the dispersion of populations in isolated islands. All of the islands shown have about the same population, sufficient
to introduce 2000­4000 new susceptible children per year. The abscissa is
1
Population input
(Land area of the archipelago in kilometers)2
which represents the average distance between infants added to the population each year. Population input is defined as
births minus infant mortality.
It has been suggested that the depopulation of the Americas
The very high mortality caused by the virus in naive
caused by these diseases led the Europeans to introduce
populations, which contrasts with the low mortality in
Africans as slaves to replace Native Americans being used
Europeans, was probably due to two causes. Europeans and
as slaves.
other Old World peoples have been continuously exposed to
measles for millennia and have been selected for resistance
5% of humans immunized with a single dose of the mea-
to measles. The people in the Americas had never experi-
sles vaccine fail to develop immunity to measles), but other
enced measles infection, however. A second factor that led
cases appear to have been due to waning immunity. Thus,
to high mortality rates was the introduction of measles into a
immunity induced by the vaccine is probably not lifelong, in
virgin population, in which not only young children but also
contrast to natural infection by wild-type measles virus. The
all of the adults were susceptible, meaning that the entire
guidelines now call for a second immunization on entry to
population became seriously ill simultaneously. This surely
elementary or middle school. This not only boosts immunity
disrupted the ability of the society to maintain itself because
in individuals whose immunity is waning, but also usually
there was no one healthy enough to care for the sick.
leads to immunity in those who did not develop immunity
after the first dose. In addition, some colleges require immu-
nization on entry. With these changes, the number of cases
Vaccination against Measles
of measles in the United States was only 100 in 1998.
At one time, measles virus was epidemic throughout the
Molecular genotyping has increased our understanding of
world and caused one of the childhood illnesses contracted
the few cases of measles that occur annually in the United
by almost everyone. Because of the extraordinary infec-
States today. In 1988­1992, all the reported isolates of mea-
tiousness of the virus, very few people escaped infection by
sles virus were subgroup 2, the indigenous North American
it. In the United States, there were about 4 million cases of
strain. However, by 1994­1995, all outbreaks were caused
measles a year, of which about 50,000 required hospitaliza-
by one of four other subgroups that are endemic in other
tion and 500 were fatal. There were 4000 cases of measles
parts of the world. Thus, these outbreaks were initiated by
encephalitis each year, with many patients suffering perma-
viremic visitors from Asia and Europe. One notable out-
nent sequelae. In addition, some fraction of children infected
break is thought to have been initiated by a single visitor to
as infants went on to develop SSPE, which is a progressive
Las Vegas and resulted in small epidemics in five states.
neurological disease that results in death within about 3
After control of measles in the United States and other
years of the appearance of symptoms. Throughout the world,
developed countries, the virus remained epidemic in many
an estimated 2.5 million children died annually of measles.
parts of the developing world. Control has recently been
Because measles was a widespread and serious disease,
established throughout most of the Americas, but measles
attempts to develop a vaccine began at about the same time as
remains a serious pathogen in other parts of the develop-
attempts to develop a poliovirus vaccine. One vaccine used in
ing world. In fact, measles is the leading cause of vac-
the United States from 1963 to 1967 consisted of inactivated
cine preventable deaths in the world. The World Health
measles virus. The vaccine was poorly protective and recipi-
Organization has initiated a campaign to eradicate measles
ents of this vaccine exposed to measles sometimes developed
but the campaign has met a number of stumbling blocks.
a more serious form of measles, called "atypical measles,"
Because the virus infects only humans in nature, it should
characterized by higher and more prolonged fever, severe skin
be possible to eradicate it using the same techniques that
lesions, and pneumonitis (inflammation of the lungs, from
were used for smallpox and that are being used for poliovi-
pneumon = lung and itis = inflammation). The increased sever-
rus. A major problem with measles, however, has been the
ity may have resulted from an unbalanced immune response
inability to effectively immunize young infants against the
primed by the formalin inactivated virus or to a lack of local
disease before they become naturally infected by the virus.
immunity in the respiratory tract (see Chapter 10). Similar
Newborns are protected from infection for 6­12 months by
problems occurred following vaccination with inactivated res-
maternal antibodies, and a live vaccine does not take while
piratory syncytial virus, a paramyxovirus described later.
they are thus protected. In many societies, measles is so per-
An attentuated measles virus vaccine, now given as part
vasive that very shortly after the infant becomes susceptible
of the MMR combination vaccine, produced much more
to infection, infection by wild-type virus occurs, thus keep-
satisfactory results. The live virus vaccine gives solid pro-
ing wild-type virus in circulation. As described in Chapter
tection from disease caused by the virulent virus and has
10, attempts to overcome maternal immunity by increasing
largely controlled the virus within the United States (Fig.
the dose of the vaccine virus have not led to satisfactory
4.10). Following introduction of the vaccine, the number of
results. New guidelines being developed recommend mul-
cases dropped dramatically. The virus continued to circulate
tiple immunizations against measles in such circumstances,
among nonimmunized individuals, however, and thousands
starting at an earlier age, in order to catch the child with the
of cases per year still occurred, sometimes associated with
vaccine as soon as it becomes susceptible to the virus.
epidemics of more than 50,000 cases. As vaccine cover-
age became more effective, cases dropped to new lows, but
Measles Neuraminidase
another epidemic in 1989­1991 caused about 50,000 cases.
This epidemic occurred in young immunized adults as well
The receptor for measles virus is a protein called CD46
as in young children who had not been immunized. Some of
that is expressed on the surface of human and monkey
the cases in young adults were due to vaccine failures (about
cells (Chapter 1), which is bound by the measles H pro-
img
Measles vaccine
licensed
500
450
400
1.0
350
300
0.5
250
200
0
1997
2002
1992
150
Year
100
50
0
1962
1967
1972
1977
1982
1987
1992
1997
2002
Year
FIGURE 4.10  Cases of measles in the United States by year. Note the difference in the scales of the two graphs. The
most recent epidemic of measles, in 1989­1991, with a total of 45,622 cases, was probably due to vaccine failure and
waning immunity in children immunized earlier with only a single dose of MMR vaccine. In 2003 a total of 56 cases
of measles was reported, of which 24 were internationally imported, and 19 were of persons exposed to the imported
infections. In 2005, a total of 66 cases of measles were reported of which 24 were imported and an additional 33 import-
linked cases were part of a single outbreak in Indiana initiated by exposure in Romania. From MMWR, Summary of
Notifiable Diseases-1998; the comparable summary for 2004; and MMWR (2006), Vol. 55, p. 1348.
tein. In view of the fact that sialic acid was not the measles
ing foxes in Australia, but from no other animal except the
receptor, the apparent lack of neuraminidase activity in the
horses infected in these outbreaks.
H protein was not surprising. Recent studies of the mor-
Nipah virus shares 83% amino acid sequence identity with
billivirus H protein have shown that it is related in struc-
Hendra virus. It is widely distributed in Southeast Asia and
ture to the HN protein of paramyxoviruses, however, and
has been isolated from fruit bats in Malaysia, Cambodia, and
that the related rinderpest and peste-des-petits-ruminants
Bangladesh. It first emerged in 1998­1999 when an outbreak
viruses possess neuraminidase activity. This neuramini-
of 258 cases of human encephalitis occurred in Malaysia and
dase activity differs in its specificity from that exhibited
Singapore that had a 40% mortality rate. The epidemic was
by the respiroviruses and the orthomyxoviruses, explain-
associated with an outbreak of respiratory disease in pigs, and
ing why it had not been observed previously. Presumably
humans infected with the disease were pig farmers or others
this activity is also found in the measles H protein, and the
closely associated with pig farming. There was no evidence
function of this enzyme in the measles life cycle remains
for human-to-human transmission in this outbreak.
to be determined.
Recent epidemics of Nipah virus encephalitis have
occurred in Bangladesh in 2001, 2003, 2004, and 2005.
In these epidemics there was no evidence for the infection
Genus Henipavirus
of an intermediate animal such as occurred in the Malasian
Two species of henipaviruses are currently recognized,
epidemic. Furthermore, in the 2004 epidemic evidence was
Hendra virus and Nipah virus. Hendra virus first emerged in
obtained that person-to-person transmission of the virus had
1994 when an outbreak of severe respiratory illness with a
occurred and it is possible that the disease was transmitted
75% fatality rate occurred in horses near Brisbane, Australia.
directly from bats to humans, possibly by human consump-
Two humans also contracted the disease, of whom one died.
tion of partially eaten fruit followed by person-to-person
Hendra virus was quickly isolated and shown to be respon-
transmission. The fatality rate in these epidemics has been as
sible for the disease. Subsequent studies established that the
high as 75%. In nearby India, an epidemic of Nipah occurred
reservoir of the virus was fruit bats called flying foxes. Small
in 2001.
outbreaks of Hendra also occurred in northern Australia
Hendra virus and Nipah virus represent emerging patho-
in 1994, 1999, and 2004. Hendra virus is widespread and
gens. They are previously unknown viruses that are caus-
antibodies to it have been found in all four species of fly-
ing serious disease over widely separated geographic areas.
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