Journal of Pathology

J Pathol 2006; 208: 199214

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1873

Review Article

Morbilliviruses and human disease

Bertus K Rima* and W Paul Duprex
School of Biomedical Sciences and Centre for Cancer Research and Cell Biology, The Queens University of Belfast, Belfast, BT9 7BL, UK

*Correspondence to: Abstract

Bertus K Rima, School of
Biomedical Sciences and Centre
for Cancer Research and Cell
Biology, The Queens University
of Belfast, Belfast, BT9 7BL, UK.
E-mail: b.rima@qub.ac.uk
Morbilliviruses are a group of viruses that belong to the family Paramyxoviridae. The most
instantly recognizable member is measles virus (MV) and individuals acutely infected with
the virus exhibit a wide range of clinical symptoms ranging from a characteristic mild self-
limiting infection to death. Canine distemper virus (CDV) and rinderpest virus (RPV) cause
a similar but distinctive pathology in dogs and cattle, respectively, and these, alongside
experimental MV infection of primates, have been useful models for MV pathogenesis.
Traditionally, viruses were identified because a distinctive disease was observed in man or
animals; an infectious agent was subsequently isolated, cultured, and this could be used to
recapitulate the disease in an experimentally infected host. Thus, satisfying Kochs postulates
has been the norm. More recently, particularly due to the advent of exceedingly sensitive
molecular biological assays, many researchers have looked for infectious agents in disease
conditions for which a viral aetiology has not been previously established. For these cases, the
modified Kochs postulates of Bradford Hill have been developed as criteria to link a virus
to a specific disease. Only in a few cases have these conditions been fulfilled. Therefore, many
viruses have over the years been definitely and tentatively linked to human diseases and in
this respect the morbilliviruses are no different. In this review, human diseases associated
with morbillivirus infection have been grouped into three broad categories: (1) those which
are definitely caused by the infection; (2) those which may be exacerbated or facilitated
by an infection; and (3) those which currently have limited, weak, unsubstantiated or no
credible scientific evidence to support any link to a morbillivirus. Thus, an attempt has
been made to clarify the published data and separate human diseases actually linked to
morbilliviruses from those that are merely anecdotally associated.
Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: morbillivirus; paramyxovirus; measles; disease; infection

Introduction the involvement of these viruses in human disease,

At first sight, the title of this review is surprising
as morbilliviruses, with the exception of measles
virus (MV), are not known for their propensity to
cause disease in humans. Nevertheless, the current
controversies about the involvement of MV in various
human diseases are best reviewed in the wider context
of the pathology of this group of viruses in their natural
hosts and the suggested involvement of morbilliviruses
in human disease.
Morbilliviruses obtained their collective name from
the diminutive form of morbus, meaning plague, and
historically, the term was particularly useful in dif-
ferentiating measles from smallpox and scarlet fever
infections [1]. As one of the six genera in the Paramyx-
oviridae family, morbilliviruses are responsible for
many severe human and animal diseases. Thus, mem-
bers infect man: measles virus (MV); cattle: rinder-
pest virus (RPV); sheep and goats: peste des petits
ruminants virus (PPRV); a wide range of carnivores:
canine distemper virus (CDV); seals: phocine distem-
per virus (PDV); and porpoises and dolphins: cetacean
morbillivirus (CeMV) [2]. As this review focuses on
we can be very brief about RPV, PPRV, CeMV, and
PDV, since in spite of their clear evolutionary rela-
tionship with MV and CDV and their potential to use
the same cell surface receptors [3,4], they have not
been implicated in any human disease. Domesticated
animals infected with RPV or PPRV could potentially
transmit very large doses of infectious virus to those
who care for them. However, this exposure has not
led to any reported or recognizable zoonosis. Possible
explanations for the lack of zoonotic infections will
be reviewed in a later section in which we review
the suggested, but unproven, involvement of CDV in
human disease. Thus, we will primarily focus on the
basic clinical aspects, molecular properties, pathogen-
esis, and involvement of MV in human disease.
Measles, the disease and the virus
The earliest descriptions of MV are found in Arab
writings of Al Rhazes in the tenth century AD [5]. Hip-
pocrates did not mention the disease amongst his oth-
erwise careful and accurate descriptions of childhood

Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
200
diseases. This has been interpreted as evidence that the
disease was not present in early human populations,
although we cannot be sure about this as measles was
often confused with other diseases, such as smallpox
and scarlet fever. At the time of Hippocrates, human
populations were probably too small and too isolated
to support endemic MV, which requires interacting
populations of 200300 000 people to supply suscep-
tible children at a sufficient rate to sustain infection
[6,7]. Measles is one of the most contagious diseases
known. The basic reproduction number (R0 ), which
indicates the number of secondary cases that can be
generated from an index case in a susceptible popula-
tion, is estimated to be more than 15 [8] and could be
much higher. Hence, the supply of susceptible children
is rapidly exhausted in small populations.
The infection is usually not life-threatening and
apart from rare but severe sequelae, there are usually
no lasting after-effects in individuals who live in the
developed world. Here, the mortality rate is approxi-
mately 1 : 1000 cases. Complications that require hos-
pitalization such as bronchiolitis and pneumonitis are
frequent, occurring in up to 10% of cases. The situa-
tion is very different in developing countries. There,
measles can have very high mortality rates (510%)
and severe morbidity is associated with the infection
[9,10]. The causes of these differences in clinical out-
come between the developed and the developing world
are not well understood. Several hypotheses have been
put forward such as the dose rate of infection [11],
immunological challenge by other infections, vitamin
status, and strain differences [12]. However, at present,
none of these offers a satisfactory explanation for the
striking differences in the clinical symptoms mani-
fested in infected children.
Measles is a very serious disease worldwide, with
a mortality of still nearly 800 000 children per annum
[13]. This is primarily associated with malnutrition and
secondary bacterial and parasitic infections. Perhaps
as many as 78 million childhood deaths occurred
annually before the introduction of the current live
attenuated vaccines and global eradication campaign
co-ordinated by the WHO [14]. Worldwide vaccination
has reduced the number of cases by about 90%. The
virus can infect many primate species, including the
great apes. However, these are dead-end hosts and the
virus can only be maintained in human populations.
It does not appear to infect other animals by natural
routes.
Molecular biology of the virus
In order to understand the pathology of MV and its
involvement in human disease, it is first necessary to
describe the molecular biology of MV. Apart from a
small number of exceptions, the life-cycles of the other
morbilliviruses are identical.
MV has a lipid membrane and as such, the viri-
ons range in size from 100 to 300 nm (Figure 1A).
J Pathol 2006; 208: 199214
BK Rima et al
Six structural proteins are present in the virions. Two
glycoproteins span the membrane and form oligomeric
spikes which are visible by electron microscopy. The
haemagglutinin (H) protein binds cellular receptors
(see later) and the fusion (F) protein mediates entry
into permissive cells by fusion of the virion and
plasma membranes. The F protein is formed as an inac-
tive precursor (F0 ), which is biologically activated by
a proteolytic cleavage involving furin-like proteases
[15]. In spite of the fact that both proteins form the
spike, as illustrated in the schematic representation
of the virion (Figure 1), the majority of neutralizing
antibodies recognize epitopes on H [16,17]. Follow-
ing receptor recognition, structural changes in the F
glycoprotein initiate virus entry, which occurs in a
pH-independent manner. However, even though the
structure of the post-fusion ectodomain of a paramyx-
ovirus fusion protein has been recently resolved, the
exact molecular details of the rearrangement remain
unclear [18]. A third hydrophobic viral protein coats
the inside membrane of the virion and is thus termed
the matrix (M) protein. It is a multifunctional protein
having a role in virus budding [19] and transcription
regulation [20]. Three remaining structural proteins
are associated with the genomic RNA and form a
helical ribonucleoprotein (RNP) complex (Figure 1B).
This is the basic unit of infectivity and is 1 m in
length and 1821 nm in diameter [21]. The nucle-
ocapsid (N) protein is the major component of the
RNP, whereas the phospho- (P) and large (L) proteins
are present in lower amounts, as illustrated in the
schematic representation of the RNP (Figure 1). Func-
tioning as both a transcriptase and a replicase, the
L protein is an RNA-dependent RNA polymerase
(RdRp) which must be incorporated into all progeny
virions.
Transcription from the non-segmented 15 894
nucleotide-long, negative sensed RNA genome com-
mences once the RNP is liberated into the cyto-
plasm. The genes encoding the structural proteins are
present in six transcription units (TUs) which are sep-
arated by non-transcribed intergenic (Ig) sequences.
A single promoter in the 3
leader is recognized
by the RdRp and transcription proceeds sequentially
by a startstop process producing polyadenylated
mRNAs. As the polymerase can detach from the
RNP after transcribing any of the genes and can
only re-access it at the promoter, a gradient of tran-
scripts is generated and relative mRNA amounts reflect
the viral gene order, ie N > P > M > F > H > L
(Figure 1C). Two additional non-structural proteins,
V and C, are encoded within the P gene and some-
times this gene is referred to as PV/C . These are
generated from a downstream overlapping reading
frame (C) and from an edited mRNA containing an
additional non-templated nucleotide inserted by RdRp
slippage (V) [22]. Reverse genetics approaches have
shown that neither is required for replication in vitro
[23,24], although perturbations in the replication of
both viruses are observed in primary cells and animal
Morbilliviruses and human disease 201

Figure 1. Schematic representation of a morbillivirus virion, ribonucleoprotein (RNP) complex, genome organization, and the six
mRNAs produced by the RNA-dependent RNA polymerase (RdRp) during transcription. (A) Electron micrograph of a nascent
measles virus virion budding from the plasma membrane of an infected cell. Virus spikes composed of the haemagglutinin (H) and
fusion (F) glycoproteins are visible on the outside of the virion and a dense area beneath the membrane is where the matrix
(M) protein interacts with the cytoplasmic tails of F and H. (B) Electron micrograph of the measles virus RNP showing the
characteristic herring-bone configuration. This is also represented diagrammatically in yellow. The RNP is composed primarily
of the nucleocapsid (N) protein and it associates with the RdRp, which is made up of the large (L) and phospho- (P) proteins.
(C) Diagrammatic representation of the nucleoprotein-encapsidated measles virus genome showing the gene order of the N, PV/C ,
M, F, H, and L structural proteins and the V and C non-structural proteins which are translated from the PV/C gene. Messenger
RNAs are indicated beneath the genome. Their abundance represents the gradient of transcripts that arises due to the startstop
mechanism of transcription from the single promoter in the 3
end of the genome

models [2527]. Inhibition of the type I interferon
response by C has been reported [28].
Replication involves the RdRp reading across the
Ig sequences to produce a full-length positive sensed
copy of the genome which is concomitantly encapsi-
dated with N protein. The resulting (+)RNP contains a
strong promoter in the 3
end which directs the produc-
tion of many more genomic () RNPs. Virus assembly
occurs in lipid rafts at the plasma membrane to where
the F and H glycoproteins move from the Golgi appa-
ratus. The M protein associates with the cytoplasmic
tails of the glycoproteins and the () RNP. Virions are
released by the cell by budding (Figure 1A), although
the stages of this process are not particularly well
understood.
Many genomic sequences have been obtained for
both wild-type and vaccine strains of MV. The virus is
monotypic, existing as a single serotype, and infection
with one strain appears to provide life-long protection
from the disease. With the development of RT/PCR
and DNA sequencing techniques, it has become clear
that virus isolates vary in their nucleotide sequences,
especially in those encoding the last 150 amino acids
of the N protein and the entire H protein [2932]. At
least 22 genotypes exist and these have been grouped
into eight clades. All vaccine viruses are genotype A.
Although these viruses may once have been geograph-
ically restricted in their distribution, the increase in
travel by children, who are the prime reservoir for
virus replication, has now allowed worldwide distri-
bution of most of the genotypes.
Pathogenesis of MV infection
Many aspects of MV infection are well understood
and viral pathogenesis is reviewed comprehensively
by Diane Griffin [33]. MV spreads from person to

J Pathol 2006; 208: 199214

202
person within aerosol droplets. The virus is extremely
infectious (see above) and a single tissue-culture
infectious dose can cause disease in monkey models
[34]. After inhalation, the virus replicates in the
upper respiratory tract, in the epithelia of the trachea
and the lung, although it is not entirely clear in
which cell types initial replication occurs. The older
literature describes that virus replicates in epithelial
cells that line the lungs and the upper respiratory
tract. However, there are also cells of the immune
system in these tissues and it is possible that these
cells are infected first. In this context, it is important to
consider what is currently known about MV receptors,
as receptor distribution is an important determinant
of pathogenesis for many viruses. CD46, also known
as membrane cofactor protein, which plays a role in
protecting cells from complement lysis, is a cellular
receptor for laboratory-adapted and vaccine strains
of MV [35,36]. In cells infected with these strains,
CD46 is down-regulated from the cell surface and
this renders the cells more susceptible to complement
lysis [37], but this is not the case in cells infected
with wild-type MV. In general, wild-type viruses use
CD150 (SLAM) as an entry receptor instead of CD46
[3,38,39]. There is still some controversy about the
usage of different receptors by different MV strains.
If wild-type viruses exclusively use CD150 [38,40],
which is not expressed on epithelial cells, this means
that they cannot be infected by the inhaled virus. In
that case, initial replication of the virus can only take
place in tissue resident lymphocytes, macrophages or
dendritic cells that express SLAM. If the wild-type
viruses are also able to use CD46, then a wider variety
of cells could be infected [41]. Recently, it has been
shown that haematopoietic stem cells express CD150
and these SLAM-positive cells have been detected in
sinusoidal endothelium in spleen and bone marrow
[42]. This opens up the possibility that MV may be
able to replicate in hitherto unrecognized cells and
tissues, and, in the future, it will be important to
examine what effect infections of such stem cells
might have on viral pathogenesis.
The second phase of the infection takes place in
the immune system as the virus infects macrophages,
lymphocytes, and possibly dendritic cells. Very few
free virions can be isolated directly from blood, which
is consistent with the highly cell-associated nature
of the virus. Most of the infectivity appears to be
associated with a small subset of macrophages and
T and B lymphocytes, and the number of infected
lymphocytes is very small (35%). The growth of
the virus in cells of the immune system leads to an
amplification of the number of virions. This causes
MV to spread to tissues either directly in the blood
or via the transfer of cell-associated virus particles
from cell to cell during the intimate contacts that
are formed between cells of the immune system
during their normal function. The mechanism by
which cell-associated virus infects other cells is not
entirely clear. It is possible that loosely attached
J Pathol 2006; 208: 199214
BK Rima et al
virions on the outside of infected cells can fuse with
uninfected target cells. It is also possible that this
leads to fusion of the cell to which the particle was
attached and the newly infected cell. This would
lead to the formation of multi-nucleated cells or
syncytia.
Lymphoid organs such as the spleen, the lymph
nodes, the appendix, and the tonsils are very important
sites for primary virus replication [43]. From here, the
virus can spread to a large number of organs including
the skin, the conjunctiva, the kidney, the lung, the gas-
trointestinal tract, respiratory mucosa, genital mucosa,
and the liver. Infection appears to initiate in these tis-
sues either by infiltration of infected macrophages and
lymphocytes or by infection of epithelial or endothelial
surfaces of these tissues that then allows propagation
of the virus and penetration to the inside of the tissues.
These processes take place during the asymptomatic
phase. By 10 days post-infection, the patient becomes
symptomatic, developing the rash that is characteristic
of the infection.
Symptoms and transmission
MV infections are characterized by a maculopapular
rash, dry cough, coryza, fever, conjunctivitis, and pho-
tophobia. A characteristic feature is the appearance of
Koplik spots, which are similar to those in the skin but
appear in the mucosal surfaces of the mouth 12 days
earlier. Delayed-type hypersensitivity responses to pre-
existing antigens, such as tuberculin, transiently disap-
pear during acute measles infection and convalescence.
The description of this phenomenon by von Pirquet in
1906 made MV the first recognized immunosuppres-
sive agent. The immunosuppression does not affect the
development of an immune response to the virus itself
or to co-administered antigens.
Much of the knowledge that has been obtained in
the area of pathogenesis comes from experimental
infection in non-human primates (see below) or ex vivo
studies, and precise details of the pathogenesis in
humans are scant. Spread to the mucosal surfaces of
the lung probably allows transmission to a new host.
The virus is also detectable in the urine of the patient,
probably as cell-associated virus, for approximately
1 week after the rash appears. This does not contribute
to person-to-person transmission of the virus. The
main route of transmission probably involves virus
shedding from immune system cells in the lung of
infected children and the aerosolization of these during
coughing.
Central nervous system (CNS)
complications of measles
Children with a well-functioning immune system over-
come the acute infection successfully and few long-
term sequelae are known. The three most serious
and severe complications occur in the CNS. These
Morbilliviruses and human disease
are acute demyelinating encephalomyelitis (ADEM),
measles inclusion body encephalitis (MIBE), and sub-
acute sclerosing panencephalitis (SSPE); the last two
are invariably fatal.
Acute demyelinating encephalomyelitis (ADEM)
ADEM occurs about 56 days after the appearance of
the rash, when 1 : 1000 infected children start to suffer
from acute encephalitis [44]. It is three orders of mag-
nitude less common in vaccinees. Infection of the CNS
has been suggested to be a normal occurrence, as wide-
spread electroencephalogram (EEG) changes are seen
in almost half of patients. However, cytokine effects
from the infection may be an alternative explanation
for these. No virus has ever been demonstrated in the
brains of children who died from the acute encephalitis
[45]. ADEM is associated with widespread perivascu-
lar demyelination of the myelin sheath of neurones
near small blood vessels in the brain, although what
and how this occurs is not clear. One suggested mecha-
nism is that it is an auto-immune reaction. However, at
present, there is no consensus opinion about the pre-
cise mechanism(s) involved. Due to its rarity, it has
been very hard to study ADEM.
Measles inclusion body encephalitis (MIBE)
The second type of CNS infection, MIBE, occurs in
immunocompromised patients between 2 and 6 months
after acute infection [46]. This can follow wild-type
virus infection as well as vaccination. Dysgamma-
globulinaemia or a pre-existing undiagnosed immune
abnormality has been found to play a role in the two
cases that were associated with vaccine strains [47,48].
This immune diathesis provided the children with only
limited ability to restrict virus infection and may have
allowed the virus to persist and reach their brain. The
mechanism of virus spread and persistence in the brain
in MIBE patients are not well understood.
Unlike SSPE (see later), MIBE is not associated
with a hyper-immune antibody response to measles
proteins and oligoclonal bands are not detected in
CNS. Recently, MIBE caused the death of a 13-year-
old boy who had been treated for chronic granuloma-
tous disease by stem cell therapy. Neither the patient
nor the stem cell donor had apparent recent measles
exposure or vaccination, and neither had visited a
region of the world where MV was endemic [49]. The
simplest explanation may be persistence of the virus in
either the donor or the recipient. Nevertheless, repeat
exposure cannot be ruled out in this case as the virus
is highly infectious.
Subacute sclerosing panencephalitis (SSPE)
Much rarer still is SSPE, which affects one in
10 00025 000 children after acute measles [50]. SSPE
predominates in males at a 2.5 : 1 ratio [51]. This dis-
ease is caused by a persistent MV infection [52]. The
203
factors that turn a normal acute infection into one
that will many years later manifest itself as SSPE are
unknown. Acquiring the acute infection under the age
of 2 is a risk factor [53]. A potential role for maternal
antibody has been postulated in the process due to the
fact that antibodies have been considered to be able
to generate persistent infection and modulate acute
infection in vitro in cell cultures [54,55]. However, no
direct evidence for this suggestion is available. Early
epidemiological studies also showed a rural prevalence
for SSPE, but that has not been confirmed in later
studies and may simply reflect changes in the pat-
terns of infection [56]. All the reliable studies on SSPE
have been carried out in countries in which measles
vaccination rates have been high. One reason for the
rural prevalence has been suggested to be the involve-
ment of co-infection with an animal virus, especially
CDV. However, there is no evidence to support this
notion. The persistent brain infection leads to a hyper-
immune antibody response and this is a pathognomic
feature of the disease. There are extremely high titres
of neutralizing antibody in both the serum and the
cerebrospinal fluid (CSF) of patients. CNS resident B
cells give rise to MV-specific oligoclonal bands and it
has been demonstrated that the antibodies present in
these have undergone affinity maturation [57]. Anti-
bodies to structural proteins such as N, F, and H are
present in amounts that exceed by ten-fold the normal
range observed in the acute infection [58]. Antibod-
ies to the M and P proteins are much less prevalent
and the lack of an immune response to M in particular
has been taken as an indicator that there are mutations
in this gene. There is no evidence for abnormalities
in cell-mediated immune responses to MV in SSPE
patients.
On average, it takes approximately 8 years after an
acute infection for the first symptoms of SSPE to
appear [59]. In the early stages, children lose attention
span and show severe neurological symptoms such as
ataxia. Then, in all cases, the disease progresses to
a situation where the child slides into a vegetative
state and dies from the infection. The disease manifests
itself in severe demyelination and profound infection
of neurones. MV-specific inclusions are present both
in the cytoplasm and in the nuclei of infected neurones
[60]. In the latter stages of SSPE, small numbers
of oligodendrocytes, astrocytes, and endothelial cells
have been shown to be infected [61]. It is assumed
that the intra-cytoplasmic inclusions represent the sites
of transcription and replication. However, the nature
of the nuclear inclusions has not been confirmed.
These could be viral RNPs but are more likely to be
complexes of viral N protein, which has been shown
to be able to translocate to the nucleus [62]. One
of the longest recorded patients carried the persistent
infection for over three decades before the onset of
symptoms. In terms of the duration of the symptomatic
period, there is a report of a 52-year-old who died
4 years after diagnosis [63]. The incidence of SSPE
J Pathol 2006; 208: 199214
204
has been significantly reduced by measles vaccination
programmes.
The defective nature of virus in SSPE and MIBE
brains
Much is known about the molecular characteristics
of SSPE viruses (reviewed by Rima and Duprex
[64]). In general, no infectious virus can be recovered
from the CNS tissue at autopsy or biopsy. Mutations
in the virus genomes have been documented by
sequencing RT/PCR products amplified from autopsy
brain material of the patients. In essence, the main
mutations observed in SSPE-derived MV render the
M, F, and the H proteins non-functional (see below),
whereas the N, P, and L proteins are relatively
unaffected. This is not surprising as the latter proteins
are essential for replication and hence absolutely
necessary to maintain the persistent state [65,66].
Mutations that reduce the ability of the virus to fuse
with cells or decrease the budding from cells are
typical and it appears that such mutations are selected
in cases of SSPE. These mutations may allow the virus
to grow in the special environment of the CNS in
which neurons are in close contact and where there
may be particular mechanisms to transfer molecules
from the cytoplasm of one cell to another as part of the
normal function. Indeed, the virus may exploit these
mechanisms to piggy back from cell to cell.
A number of mechanisms have been identified
which lead to a decrease in the amount of M protein
expressed. Generation of bicistronic mRNAs from the
P and M genes during transcription by polymerases
which ignore the Ig sequences leads to a signifi-
cant decrease in the number of monocistronic tran-
scripts which can be utilized to produce the M protein
[67,68]. As the second open reading frame (ORF) in
the bicistronic mRNA is inaccessible to the ribosomes,
this should further decrease M protein concentrations.
In addition, there is a general perturbation in the rela-
tive levels of mRNAs during MV transcription in cells
of the CNS. This affects the steepness of the gradi-
ent of gene expression, leading to significantly lower
levels of F, H, and L proteins. This could allow the
virus to evade detection by the immune system and
limit the release of virions [67,69]. Sequencing studies
have identified many nucleotide changes in the M gene
such as alterations to the initiation codon, hypermuta-
tion events, and insertion of premature stop codons
[65,68,7072]. Biochemically, the resulting proteins
are more susceptible to proteolytic degradation and
have decreased stability. Recombinant viruses have
been generated in which the M gene has been deleted.
The viruses are highly cell-associated, are more neuro-
invasive, but less virulent in a transgenic mouse model
[73]. This leads to a decrease in the mortality of the
animals.
Mutations are also common in the gene that encodes
the F glycoprotein. These tend to cluster in the cyto-
plasmic tail, which is highly conserved in all morbil-
liviruses. Sequencing studies have identified premature
J Pathol 2006; 208: 199214
BK Rima et al
stop codons and nucleotide deletions that cause frame-
shifts [74]. These truncations and extensions of the
cytoplasmic tail are predicated to interfere with an,
as yet, unidentified function which may be connected
to virus budding or lipid raft targeting. For example,
it is known that a specific tyrosine is important as a
basolateral sorting signal [75]. In a recombinant virus
in which the MV F and H glycoproteins have been
replaced by the vesicular stomatitis virus G glycopro-
tein [76] the M protein is absent from the virions.
Although the virus grew to low titres this suggests
that the cytoplasmic tails of F and H interact with
M and that the protein is not essential for budding.
Other recombinant viruses which lack only the cyto-
plasmic tails also showed lower levels of virulence
in vivo [73,77].
Recognition of MV genotypes allows sequences
obtained from SSPE material to be compared with
wild-type and vaccine viruses. To date, no sequences
from SSPE cases have been recognized as vaccine-like
(ie genotype A). Furthermore, the sequences are typi-
cally related not to the currently circulating wild-type
viruses, but to those in circulation when the individ-
ual developed the acute infection as an infant. These
observations confirm that SSPE represents the prime
example for the long-term persistence of an RNA virus
in the human and that it is not caused by MV re-
infection [78,79] (P Rota, personal communication).
This is also consistent with the fact that an acute MV
infection confers life-long immunity to the individual.
Interestingly, although it is clear that SSPE is caused
by MV, what has not been established is where the
virus resides and replicates in an individual during
the intervening 812 years. Thus, the commonly held
belief that the virus is present in the CNS has not been
formally proven. What is currently known about the
viral receptors argues that the site of persistence may
not be in the CNS, as the major cell types in which
the virus replicates (neurones and oligodendrocytes)
do not express SLAM at detectable levels [80].
Other known complications of measles
One of the main complications of acute measles is
interstitial pneumonitis and mucosal inflammation in
the respiratory tract [81]. Giant cell pneumonia is
much more clinically significant and is primarily a
feature in immunocompromised people. Large giant
cells are caused by fusion of infected cells with
neighbouring cells. The resulting destruction of the
epithelium leads to bronchial pneumonia and this
is usually associated with damage to the lungs and
hospitalization of the children. Normally, this will
resolve and no long-term damage ensues.
MV induces a clinically significant immunosuppres-
sion [8284]. The mechanism by which immuno-
suppression occurs is not clear but both long-lived
cytokine imbalances and direct effects on the prolifera-
tion of lymphocytes have been demonstrated. It is also
Morbilliviruses and human disease
possible that haematopoietic stem cells are deleted in
the infected individual as these express CD150 [42].
The latter two mechanisms may explain the marked
lymphopenia associated with the disease.
Immunosuppression has been suggested as the prob-
able cause of many of the complications of measles.
For example, it is not clear whether the occurrence
of diarrhoea is caused by virus-induced damage to
the epithelia in the gastrointestinal tract or whether it
results from the virus-induced immunosuppression and
subsequent secondary infections. Diarrhoea is most
common in the developing world, where inter-current
bacterial and parasitic infections are frequent, and
is much less common in the developed world. Oti-
tis media and laryngo-tracheo-bronchitis are possibly
other manifestations of secondary infection associated
with the virus-induced immunosuppression.
Blindness and MV infection
Although the mortality associated with MV infections
is often cited, it is much less commonly reported
that the virus is the leading cause of blindness in
the developing world [85]. Conjunctivitis is common
in nearly all affected individuals, irrespective of their
socio-economic status. Patients demonstrate swelling
around the eyes and are photophobic. Viral RNA can
be detected in tear secretions by RT/PCR [86]. Corneal
inflammation (keratitis) affects a significant proportion
of individuals. If the patient has a balanced diet and
lives in the developed world, long-term ocular defects
are rare [87]. However, oftentimes this is not the
case in developing countries, where malnourishment
and particularly vitamin A deficiency are associated
with severe keratitis. This is due to the fact that
the integrity of the eye is compromised, as, for
example, mucins are present in lower levels in such
individuals. Secondary infections, both bacterial and
viral, are known to exacerbate MV-induced corneal
complications. The spectrum of clinical manifestations
associated with MV infection is similar to that linked
to vitamin A deficiency; thus, high-dose capsules
(200 000 IU) are provided twice a year and food
fortification programmes have been promoted [88,89].
Furthermore, vitamin A is prescribed to children
hospitalized due to a MV infection on admission,
re-administered the following day, and again in the
following month. Most vaccination programmes in the
developing world also include co-administration of
vitamin A. This simple treatment is highly efficacious
in facilitating the resolution of corneal ulceration. The
precise mechanism of vitamin A action in MV-infected
individuals is not clear but several clinical trials have
confirmed its efficacy in reducing mortality.
Infection of the cornea highlights one of the key
conundrums of MV pathogenesis, namely that cells
which lack the currently identified receptors (specif-
ically SLAM) can be infected by wild-type viruses.
It is clear that wild-type viruses utilize SLAM
and this receptor is not detected on cells of the
205
corneal epithelium. To the best of our knowledge,
no study has presented unequivocal double-stained
immunohistochemical data demonstrating direct infec-
tion of corneal epithelial cells. This paradox is mir-
rored in the CNS, where again neurones, which also
are not known to express SLAM, can be infected in
SSPE (see above). MV-induced pathology has also
been observed in the retina and optic nerve, and
some SSPE patients initially present with a loss of
vision [90,91]. In one case, an initial diagnosis of
an acute multifocal placoid pigment epitheliopathy-
like lesion was made, as a white infiltration of the
macular area and papillary oedema were observed
[92]. However, subsequently, progressive neurological
defects were observed and the diagnosis was revised
to SSPE. Multifocal sub-retinal lesions have also been
reported in patients previously diagnosed with SSPE
and histopathological analysis has identified RNP-like
structures in retinal samples [93].
Hearing loss and measles infection
Loss of hearing is commonly associated with MV
infections [94]. A key complication is otitis media,
which occurs in up to 10% of individuals who have
been hospitalized due to the acute infection [9597].
The mechanism by which this occurs is unknown and
again it could possibly be due to the virus-mediated
immunosuppression, which allows opportunistic sec-
ondary infections in the middle ear by decreasing lev-
els of IgG and IgM within this compartment. However,
whether this occurs directly or indirectly is unclear
[98]. Pathological changes have been reported in four
individuals with severe necrotizing otitis media who
died due to secondary bronchopneumonia, indicating
that the virus may directly infect the middle ear [99].
Moreover, multi-nucleated cells were detected in one
of these cases, although neither MV antigen nor RNA
was detected.
The middle ear fluid (MEF) is kept sterile by
immune mechanisms involving B lymphocytes and
antibody. The B lymphocytes that produce the
immunoglobulins may originate from the mucosal-
associated lymphoid tissue or the cells may enter the
middle ear mucosa from the vasculature. If antibody
secreted into the MEF is derived from serum antibody,
then it is unlikely that localized measles infection will
be able to suppress this significantly. However, Sloyer
et al [100] suggested that the mucosa lining the middle
ear cavity is an active epithelium that locally produces
antibodies and the skewed ratio of MEF to serum IgA
supports this. Direct MV infection in the antibody-
producing cells might compromise the sterility of the
MEF. Evidence for local production of IgA against
MV in 16 out of 41 cases of otitis media was reported
[100]. However, in an equal number of cases, the IgA
detected was against poliovirus, and in four and five
cases, against mumps and rubella virus, respectively.
This suggests that the reaction is probably not MV-
specific.
J Pathol 2006; 208: 199214
206 BK Rima et al

Damage to the cochlear sensorineural elements
or to the cochlear nerve is known to result in
permanent deafness. Historically, sensorineural loss
has been linked to ADEM [101] and pathological
alterations have been reported to occur in the inner ear
[94,102104]. However, to this day, the precise role
that MV plays in irreversible deafness is uncertain, as
neither viral antigen nor RNA has been detected in
samples from the inner ear. In addition, it is not clear
if the pathological changes are due to the virus directly
infecting particular cells or are caused indirectly due
to the associated inflammatory response and bystander
effects or to virus-induced autoimmunity [105].
Thrombocytopenia
Thrombocytopenia and seizures occasionally occur
after measles infection. Both resolve quickly and long-
term consequences are rare. The live attenuated vac-
cine induces thrombocytopenia in less than 1 per
20 000 vaccine doses [106,107]. These complications
are much more common after infection with wild-type
MV strains and thus the vaccine has a protective effect
against this complication. An auto-immune mecha-
nism has been proposed to explain this phenomenon
but the evidence for this remains scarce [108,109]. It
has long been recognized that MV infection and other
viruses are associated with the generation of auto-
antibodies to a number of antigens including smooth
muscle antigens and nuclear antigens. In general, this
appears to be a non-specific transient effect that dis-
appears 34 weeks post-infection.
Diseases that have been speculatively
associated with MV infection
Due to its ability to establish persistent infection
and the paradigm of SSPE, MV has been sug-
gested to have an association with a large num-
ber of diseases (Table 1). Thus, often single and
unconfirmed reports have suggested an association
with achalasia, insulin-dependent diabetes, thyroidi-
tis, and Kawasakis disease. These suggestions have
not been investigated extensively. Other suggested
sequelae of MV infection which have been subject to
more study are multiple sclerosis, epilepsy, systemic
lupus erythematosis, chronically active auto-immune
hepatitis, Pagets disease, otosclerosis, autism, inflam-
matory bowel diseases such as Crohns disease, and
ulcerative colitis [110]. However, no confirmed evi-
dence has been presented to substantiate these associ-
ations, let alone prove a causal relationship between
these diseases and MV infection. These unsubstanti-
ated associations have had a significant effect on the
uptake of measles vaccines and hence the studies that
suggest these links are reviewed here in detail.
Systemic lupus erythematosis
Measles has been suggested to play a role in systemic
lupus erythematosis (SLE). The only evidence to sup-
port this claim is the detection of MV nucleic acids in
tissue samples, and no other virological data, serolog-
ical or epidemiological evidence exist to support the
link. The disease is characterized by the presence of
anti-nuclear antibodies and antibodies to the La pro-
tein [111]. An early study demonstrated the presence
of MV-specific RNA in peripheral blood mononuclear
cells (PBMCs) [112]. However, this has not been con-
firmed [113] and it is most likely that the probes used
in the early studies were contaminated with cellular
sequences, as they were made by direct labelling or
reverse transcription of RNA from purified virus or
from purified MV-specific mRNA. One study using a
cloned probe [114] indicated by dot blot the presence
of MV RNA in 28 out of 34 SLE patients and not in 29
controls. A study using the more sensitive S1 nuclease
protection assay was not able to confirm the presence
of MV-specific RNA in the PBMCs of SLE patients
[115]. However, to the best of our knowledge, RT/PCR
has not yet been applied. The absence of other strands
of evidence and lack of confirmation of the earlier data

Table 1. Human diseases in which morbilliviruses have been suggested to play a role
Anecdotally linked or
Link possibly due to Linked on the basis of Linked on the basis of no evidence using
virus-associated largely unconfirmed or single unconfirmed modern diagnostic
Link established immunosuppression flawed evidence reports techniques

Acute demyelinating Otitis media Multiple sclerosis (MV and CDV) Epilepsy Achalasia
encephalomyelitis
Diarrhoea Pagets disease of bone (MV and Autism Thyroiditis
Measles inclusion CDV)
body encephalitis Systemic lupus Juvenile-onset
Otosclerosis erythematosis diabetes
Subacute sclerosing
panencephalitis Auto-immune chronically active Kawasakis disease
hepatitis
Thrombocytopenia
Crohns disease

Ulcerative colitis

J Pathol 2006; 208: 199214

Morbilliviruses and human disease
have probably diminished enthusiasm for carrying out
such studies.
Epilepsy
A single case report from the Kawashima group [116]
presents data obtained from a patient who presented
with epilepsy 9 years before samples were taken
(PBMCs and CSF). The patient had been vaccinated
at 12 months with MV. However, the virus detected
was a wild-type that had circulated at the time of first
presentation. All controls from patients with multiple
sclerosis (one), measles encephalitis (3 years after first
presentation; one), epilepsy after measles infection
(one), HIV encephalopathy (one), and Lennox Gastaut
syndrome (two) were negative. These samples were
obtained from individuals who had been vaccinated
against or naturally infected with MV within the
previous year. Control PBMCs and CSF from an
SSPE patient were positive. This study has not been
confirmed, nor have there been follow-up studies from
the same group.
Auto-immune chronically active hepatitis
MV was first implicated in this condition when dot-
blot hybridization was used to detect genome in lym-
phocytes using a 50-nucleotide-long oligonucleotide
probe complementary to a region of the nucleocapsid
gene [117]. This study has several technical short-
comings and it is generally accepted that dot-blot
hybridization is not sensitive, is susceptible to arte-
facts, and is not a robust method for demonstrating
what the authors claim to have shown specifically
that 12/18 auto-immune chronically active hepatitis
patients were MV RNA-positive as well as 1/3 SLE,
2/4 cryptic cirrhosis, and 0/37 controls.
Another study examined samples from two adult and
four paediatric cases [118]. A sequence corresponding
to a wild-type strain only circulating in the early 1990s
was identified from a 53-year-old individual. As this
person would almost certainly have been exposed to
measles in Japan, finding such a virus is very surpris-
ing. The other sequence obtained from a 60-year-old
could not be typed at the time. However, further anal-
ysis shows that this sequence is most similar to clade
A, to which only vaccine viruses belong. This person
would not been vaccinated, therefore they could only
have been infected at an early age by an unidentified
wild-type strain from clade A. Limited sequence infor-
mation was provided from the samples obtained from
the children. All of these sequences corresponded to
vaccine viruses.
Multiple sclerosis
Multiple sclerosis (MS) is the most common neurolog-
ical disease of young to middle-aged adults. Its preva-
lence can be has high as 1 in 200 women [119] but
wide geographical differences occur with an increas-
ing prevalence the further one is from the equator.
207
There are genetic factors involved in the disease and
it is especially prevalent among Caucasians [120].
These have not yet been characterized, although spe-
cific HLA types are present at a higher than expected
frequency in patients. Epidemiological evidence based
primarily on migration studies has been consistent in
indicating that an environmental factor encountered
before the age of 15 is involved in triggering the
disease itself or generating a predisposition for it to
be acquired at a later age [121].
A large variety of DNA viruses, especially human
herpes virus 6, and RNA viruses from many different
families, for example, human T-cell leukaemia virus 1
and human endogenous retroviruses, have been studied
for their association with MS. None has received more
attention than MV [122,123]. Increased levels of anti-
bodies to a number of viruses including measles have
been observed in serum and CSF samples [124,125].
However, these appear to be non-specific reactions,
as antibodies to a number of other viruses are also
increased. MV-specific T-cell responses in MS are less
clear as both increases [126] and decreases [127] have
been reported. The patients appear to have a constant
Th1 -biased cell-mediated response [128] and evidence
that administration of interferon gamma exacerbates
the disease has been presented [129]. Direct evidence
for the presence of viral nucleic acids is scant and
where they have been found, they were almost always
also present in control brains.
Haase et al showed that samples from 1/4 MS
patients were positive for MV sequences using in situ
hybridization (ISH) [130]. RNAse pretreatment was
shown to abrogate the signal. However, the probe
was generated from radioactively labelled cDNA made
from viral genomic RNA. This methodology is unac-
ceptably non-specific, as ribosomal and cellular RNAs
cannot be reliably removed. Our group has demon-
strated positive ISH in four out of 14 MS cases and
one case of cytomegalovirus infection but not in 56
neurological and non-neurological controls [131]. Pos-
itive signals were only detected in a small number
of foci in the MS brains and attempts to confirm
these data with other techniques such as RT/PCR have
been unsuccessful [132,133]. This may be because
viral RNAs could be diluted extensively by cellu-
lar RNA. However, the very small number of foci
of infection detected by ISH calls into question the
aetiological and pathogenic role of MV. At a recent
meeting [134], it was still considered likely that an
infection triggers MS in genetically predisposed indi-
viduals. However, there is a consensus that persistent
infection by MV as in SSPE or MIBE is unlikely to
be involved because it has been difficult to confirm
isolated reports of MV-positive reactions in ISH or
immunocytochemistry (ICC). Whether the virus can
act alone or in concert with other agents, or as part of
a series of infections in triggering auto-immune reac-
tions to myelin components remains to be investigated
further, although the involvement of any agent in such
J Pathol 2006; 208: 199214
208
a hit and run scenario is experimentally very difficult
to establish.
Otosclerosis and Pagets disease of bone
Otosclerosis (OS) is a disease that leads to partial or
severe deafness due to the irregular growth of bones,
primarily the stapes, in the middle ear. Bones grow
abnormally due to a defect in metabolism that affects
the fine balance between bone deposition and resorp-
tion. A similar imbalance gives rise to Pagets disease
(PD), which can affect many other bones in the body.
Both diseases have a significant genetic component
and chromosomal changes have been identified in each
[135,136]. However, the genes involved differ between
OS and PD. Some HLA haplotypes are associated
with OS, as would befit a viral disease. Pathological
assessment of tissues from OS patients suggest that
a long-lived inflammatory process may cause spon-
geolytic bone [137,138]. Interestingly, MV has been
proposed to play a part in both diseases and virus per-
sistence has been suggested to cause this inflammation
[139,140]. However, studies which examined MV anti-
body levels have been at variance [141143]. A num-
ber of studies have identified paracrystalline arrays in
osteoblast cells isolated from OS patients [144]. These
have been suggested to be paramyxovirus-like RNP
structures (Figure 1B), although such macromolecular
assemblies have been identified in familial expansile
osteolysis, a disease with a clear genetic cause [145].
Such structures have also been identified in osteo-
clasts in tissues obtained from patients with PD [146].
When samples from both diseases were examined by
immunohistochemistry, conflicting data were obtained
which suggested that MV, mumps virus or respira-
tory syncytial viruses were present [144,147] and these
observations were not confirmed in other studies [148].
Molecular approaches have been used to detect viral
RNA in PD and OS samples [149,150]. However,
when the amplicons were sequenced, this showed in
all cases that the viruses belonged to genotype A.
No wild-type sequences were obtained, which argues
against vaccination being responsible for a delay in
OS presentation [151]. In PD, some nucleotides dif-
fered from the published vaccine strain, although when
five of these were examined more closely [152], they
were due to errors in the sequence used for com-
parison. Others have not been able to identify MV
RNA in samples from patients with PD [152154].
The situation in OS is equally unresolved, as some
have provided evidence that MV RNA is present in
bone samples [140,143,155] and others have not been
able to confirm these data [156]. Therefore, at present,
the involvement of MV in these diseases is at best
unsubstantiated.
Inflammatory bowel disease
The link between MV and inflammatory bowel dis-
ease (IBD) has mainly been propagated by Andy
J Pathol 2006; 208: 199214
BK Rima et al
Wakefield and his colleagues [157,158]. Although they
themselves have published negative findings in rela-
tion to this link using RT/PCR [159], they considered
that the ultimate sensitivity and positive proof were
given in a paper by the Kawashima group [160]. A
recent collaborative study indicated that the sensitiv-
ity of the methods employed in the Kawashima lab-
oratory was low, leading to the suggestion that the
previous results were either false positives or due to
cross-contamination [161]. This is supported by the
fact that no evidence of MV RNA was found in the
gut samples of IBD cases [162] and Wakefield and
colleagues consigned them to the control group in the
latter paper.
Autism
Wakefield et al also published an inference in The
Lancet in 1998 about a putative link between the
measles, mumps and rubella (MMR) vaccine and
autism [163]. This inference has been withdrawn
by the majority of the original authors [164], but
Wakefield and colleagues continued attempts to find
evidence for the presence of measles in the gut of
autistic children. They proposed that the presence of
the virus would cause a leaky gut epithelium which
would allow opioid peptides to enter the bloodstream.
These peptides, after crossing the bloodbrain barrier,
were suggested to interfere with the normal function
and/or development of the CNS. No supporting or
confirmed evidence for this chain of events has been
provided. A single paper directly relating to this [162]
has been extensively commented upon on the journal
Molecular Pathologys website. From a virological
viewpoint, the data are unconvincing as the authors
have used research tests that were not validated.
This applies especially to the in situ RT/PCR assays,
which lack specificity and are notoriously difficult to
perform, as evidenced in the paper by the very poor
signal in the SSPE controls. Furthermore, only the F
gene was detected, which is surprising as it is in a
promoter distal position and therefore its mRNA levels
would be much lower than the preceding three genes
(Figure 1C). As such, there is no evidence to suggest
that MV vaccination plays any part in the development
of autism.
The role of canine distemper virus (CDV) in
human disease
CDV has been postulated to play a role in MS pri-
marily on the basis of epidemiological evidence that
has, as yet, not been confirmed. Thus, it is hypoth-
esized that the geographical distribution in incidence
is due to the stability of CDV, which would decrease
towards the equator [165]. An MS link was also pro-
mulgated as a result of the so-called MS outbreak
that followed the invasion of the Faroe Islands by
British troops during the Second World War. It was
hypothesized that infected dogs brought CDV to the
Islands and that this was responsible for the ensuing
Morbilliviruses and human disease
MS outbreak. However, evidence for the existence
an outbreak, and for the diagnosis of canine dis-
temper, has been questioned. The evidence for the
ability of CDV to cause systemic infection in human
beings is also very weak. Morbilliviruses are readily
cross-neutralized and this has been exploited in the
past in using measles vaccine to protect cattle from
rinderpest when no appropriate vaccine was available.
Hence the fact that most of the human population
would have been exposed to MV at an early age
and probably would have carried a maternal antibody
against MV that could also neutralize CDV would hin-
der or prohibit infection by CDV. Cook et al [166]
suggested a link to CDV but this has not been con-
firmed. Their studies were confounded by the cross-
reactivity of CDV with MV-specific antibodies and the
general non-specifically elevated levels of viral anti-
bodies found in MS patients. Recently, brain samples
from patients with MS were examined by immuno-
cytochemistry (ICC) using MV and CDV monoclonal
antibodies [167]. All sections were negative except for
one antibody, which bound to 8/9 MS plaques and 2/5
herpes simplex virus encephalitis brain samples, but
not six controls or four patients with ischaemic stroke.
However, no evidence for the presence of MV in MS
plaques was obtained by RT/PCR, calling into question
the specificity of the antibody. The authors suggested
that the monoclonal antibody may recognize an epi-
tope on an as yet unrecognized morbillivirus present in
the human CNS that might be implicated in MS patho-
genesis or represent a protein that is up-regulated dur-
ing inflammation. The latter is most likely the correct
interpretation, as Sheshberadaran and Norrby identi-
fied a cross-reacting epitope on a 79 kD stress protein
[168].
CDV has also been proposed to play a role in
PD based on epidemiological evidence of higher
than expected dog ownership in the North of Eng-
land amongst patients, compared with age- and sex-
matched controls [169]. Other studies were not able
to confirm these observations [170]. Nevertheless, it
led to a number of studies looking for CDV in Pagetic
bone tissues. RT/PCR on RNA samples extracted from
decalcified bone indicated that CDV was present in 8
of 13 samples but MV was not detected. When the
amplicons were sequenced, they were identical to the
Onderstepoort strain and not to wild-type strains of
CDV. The significance of these results is not clear and
contamination cannot be ruled out. Several other stud-
ies have not been able to confirm the presence of CDV-
specific RNA in nucleic acids extracted from bone,
but of course in science it is formally impossible to
prove the absence of anything [152,154]. ISH studies
using CDV-specific probes were carried out [171]. The
data appear consistent but the specificity was not high
and only 41% of the PD samples were positive with
probes for the N and F mRNAs of CDV, even though
probes for all genes and anti- and genomic RNA were
used. The latter may be explained by the much higher
copy numbers of mRNA than genomic RNA present
209
in infected cells. Alternatively, it may be a techni-
cal defect in the study, as the authors were similarly
unable to detect genomic RNA in dogs with metaphy-
seal osteopathy, whereas mRNA probes showed posi-
tive results. Signals were observed not only in osteo-
clasts, but also in osteocytes and osteoblasts, whereas
the paracrystalline arrays (see above) were observed
only in osteoclasts. Recently, Hoyland et al compared
in situ RT/PCR, ISH, and RT/PCR for CDV detection
in Pagets disease [172]. Only in situ RT/PCR was
positive in all ten bone samples and not in controls.
As commented on above, it is notoriously difficult
to obtain specific responses using this technique and
hence it must be concluded that the link between CDV
and PD is far from established.
The value of animal model systems
One of the major drawbacks in research on MV is
that the available animal models only mimic part of
the symptoms and pathogenesis of the disease in the
natural host. Mouse models have only shown viral
replication after intracerebral infection and mostly
only using rodent neuro-adapted strains. Transgenic
mouse models in which an MV receptor is expressed
show little pathology or peripheral infection. When
the expression is combined with knock-out of the
type I interferon receptor, limited pathology occurs
[173]. Mice expressing SLAM under control of the
lck proximal promoter, which directs gene expression
exclusively in T cells, also do not show a great deal of
pathology [174]. These results have been explained by
the observation that mouse cells appear to lack specific
factors required from MV replication [175]. The cotton
rat model mimics aspects of immunosuppression of
MV in the human [176,177]. The most realistic model
that mimics MV infection in humans is that of
infection in macaques [34,178184], but the cost of
these animals is high and small numbers are available.
Rash is shown as a reliable indicator of the value of
a model. More studies in macaques are needed of the
infection and pathogenesis of wild-type MV viruses
that have been passaged in such a way as not to lose
virulence. So far, the groups have concentrated on
immunological parameters or pathogenesis but more
holistic studies that integrate pathogenesis, virological,
and immunological aspects are needed.
The pathogenesis of CDV has been studied in dogs
and more recently in ferrets, as the latter provides
a more tractable animal model. Moreover, CDV has
been suggested to be a model for MS [185]. RPV
infection has been analysed in cattle to a limited extent
as this is a rather expensive model [186]. Furthermore,
studies can be hampered by the lack of immunological
reagents.
The development of systems during the last decade
which permit the generation of recombinant MVs,
virus rescue [187], has opened the door to mechanis-
tic studies, not only of MV persistence and its role in
neurological sequelae of MV infection and the role of
J Pathol 2006; 208: 199214
210
specific genes in this process, but also dissection of the
roles of individual genes in isolation or in combination
with others, in attenuation, virulence immunosuppres-
sion, and interaction with the innate immune system.
Conclusion
Morbilliviruses have been associated with an eclec-
tic assortment of human diseases. In this article, we
have aimed to review the unequivocal, circumstantial,
anecdotal, and often erroneous evidence which links
morbilliviruses to particular diseases beyond an un-
complicated acute infection, a hallmark rash, and dis-
tinctive immunosuppression. Thus, it is clear that a
direct link has been unequivocally established between
MV and ADEM, MIBE, SSPE, thrombocytopenia,
blindness, and hearing loss. It is also apparent that
continuing to study rare conditions such as SSPE may
shed valuable light on long-term persistent viral infec-
tions. This is all the more important as we further
develop and utilize stem cell therapeutic approaches,
as is indicated by the individual who developed MIBE
after such an intervention. Indirect links to MV via the
characteristic immunosuppression caused by the virus
can be made to otitis media and diarrhoea. Once again,
this demonstrates the utility of continuing to address
the underlying molecular mechanisms of the profound
immunosuppression induced my MV. We are not con-
vinced from the published data that it is valid at this
point in time to link any morbillivirus with multiple
sclerosis or Pagets disease. Likewise, the evidence
associating the MV with otosclerosis, auto-immune
chronically active hepatitis, Crohns disease or ulcer-
ative colitis remains unconfirmed. Single unsubstanti-
ated reports have associated MV with epilepsy, autism,
and systematic lupus erythematosis. No other groups
have been able to replicate the work and as such,
these reports can be given little credence. Finally,
the anecdotal or historical association of MV infec-
tion to juvenile-onset diabetes and Kawasakis disease
needs to be either compressively examined using cur-
rent molecular biological techniques or consigned to
the increasing set of reports that have circumstantially
linked all kinds of viruses to all kinds of human dis-
ease.
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