Journal of Pathology

J Pathol 2015; 235: 253–265 INVITED REVIEW

Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.4457

Pathological consequences of systemic measles virus infection

Martin Ludlow,1 Stephen McQuaid,2 Dan Milner,3,4 Rik L de Swart5 and W Paul Duprex1*
1 Department of Microbiology, Boston University School of Medicine, MA, USA
2 Tissue Pathology Laboratories, Belfast Health and Social Care Trust, Northern Ireland
3 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
4 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
5 Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands

*Correspondence to: W Paul Duprex, Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118,
USA. E-mail: pduprex@bu.edu

Abstract
The identification of poliovirus receptor-like 4 (PVRL4) as the second natural receptor for measles virus (MV)
has closed a major gap in our understanding of measles pathogenesis, and explains how this predominantly
lymphotropic virus breaks through epithelial barriers to transmit to a susceptible host. Advances in the development
of wild-type, recombinant MVs which express fluorescent proteins making infected cells readily detectable in living
tissues and animals, has also increased our understanding of this important and highly transmissible human disease.
Thus, it is timely to review how these advances have provided new insights into MV infection of immune, epithelial
and neural cells. This demands access to primate samples that help us understand the early and acute stages of
the disease, which are challenging to dissect due to the mild/self-limiting nature of the infection. It also requires
well-characterized and rather rare human tissue samples from patients who succumb to neurological sequelae to
help study the consequences of the long-term persistence of this RNA virus in vivo. Collectively, these studies
have provided unique insights into how the use of two cellular receptors, CD150 and PVRL4, governs the in vivo
tissue-specific temporal patterns of virus spread and resulting pathological lesions. Analysis of tissue samples has
also demonstrated the importance of differing mechanisms of virus cell-to-cell spread within lymphoid, epithelial
and neural tissues in the dissemination of MV during acute and long-term persistent infections. Given the incentive
to eradicate MV globally, and the inevitable question as to whether or not vaccination should cease in light of the
existence of closely related morbilliviruses, a thorough understanding of measles pathological lesions is essential.
Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: measles virus; cell-to-cell spread; immune system; epithelium; central nervous system

Received 22 August 2014; Revised 30 September 2014; Accepted 3 October 2014

No conflicts of interest were declared.

Introduction make it timely to update and consolidate the current

It has been estimated that 7–8 million children died each
year due to measles virus infections in the pre-vaccine
era. That there were 122 000 measles deaths globally
in 2012, and that vaccination resulted in a 78% drop
between 2000 and 2012 worldwide, is a testament
to the perseverance and commitment of the World
Health Organization (WHO). Currently, WHO aims to
reduce the overall mortality rate in under-5 year-olds by
two-thirds between 1990 and 2015 [1]. Over 1 billion
children have been vaccinated against measles and
other childhood diseases since 2000. The Measles and
Rubella (M&R) Initiative proposes, by 2015, to reduce
measles related deaths by 95% compared to the year
2000 levels, and to eliminate the virus from at least five
designated WHO regions by 2020 [2]. These impressive
achievements in the public health arena, alongside a
number of significant advances in our understanding of
MV pathogenesis at the molecular and cellular levels,
Copyright © 2014 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
understanding of MV pathology.
The history of measles spans a millennium since the
prototypic morbillivirus MV was first described by Al
Rhazes of Baghdad [3]. Exactly when the virus first
entered a human population is debatable, and its origin is
even less clear. However, it is certain that endemic trans-
mission requires populations sizes of several hundred
thousand individuals [4], due to the basic reproductive
number (R0 ) of the virus (∼15–17), which is one of the
highest for any human pathogen [5,6] and the fact that
MV infection leads to lifelong immunity [7]. This high
level of transmissibility also demands that vaccination
rates of >95% are achieved to ensure herd immunity
[8]. It is generally accepted that MV, like many other
human pathogens, crossed the species barrier from an
animal reservoir. Rinderpest virus is closely related to
MV and has been suggested to be the progenitor of the
human infection, although this is purely speculative
[9,10]. Closely related morbillivirus sequences have
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254
been found in vampire bats in South America [11]
and elsewhere [12], suggesting other possible origins.
Although the evolutionary origins of MV are uncertain,
this virus has evolved to become a pathogen of primates,
with humans being the only species present in sufficient
numbers to maintain endemic transmission [4,13].
In 2010 the WHO ad hoc Global Measles Advisory
Group determined that it is possible to eradicate MV,
and a timeline will be set in 2015 [2]. To achieve this,
it will be critical to attain and sustain high levels of
immunity using a two-dose vaccination schedule. This
is a challenge in both the developed and the develop-
ing world, albeit for differing reasons. Logistics, vaccine
refrigeration, donor ‘fatigue’, ensuring a consistent sup-
ply of vaccine at an appropriate cost, and the fact that
a single dose of MV vaccine still leaves some child-
ren unprotected, are some of the major challenges in
the developing world. Complacency, unfounded links
between MV vaccination and a disparate array of uncon-
nected conditions and diseases [14], lack of education
about the seriousness of the disease, and a degree of
mistrust in the medical establishment have had a signif-
icant impact on vaccine uptake in Europe and the USA,
where the target of cessation of endemic MV transmis-
sion was attained in 2000 [15]. Consequently, measles
cases in the USA have reached a 20 year high in 2014,
with 593 infections in 18 outbreaks representing nearly
90% of cases; this is the highest number since MV
was eliminated in 2000 [16]. During the most recent
12 month reporting period, 30 European countries per-
forming measles surveillance recorded nearly 10 000
cases, with Germany, Italy, The Netherlands, Romania
and the UK accounting for just over 90% of these [17].
Unsurprisingly, the majority of affected individuals were
unvaccinated, which remains a major challenge for pub-
lic health and policy makers alike, given the drive to
eradicate the virus.
Animal models and human tissues: pragmatic
pathology
Although measles is primarily a human disease,
non-human primates are also susceptible to natural
MV infection [18,19]. Clinically, cough, conjunctivitis
and coryza, colloquially the ‘three Cs’, are observed
at the end of the prodromal phase in humans, and
these mild symptoms precede the hallmark Koplik
spots in the cheeks, and rash which spreads from the
face to the extremities over subsequent days. Pyrexia
is also a common early sign of the infection and
lasts approximately 1 week. The disease course is
usually self-limiting and resolves after 3 weeks. As
such, there is very limited clinical material available
from human cases in the prodromal [∼10–14 days
post-infection (d.p.i.), early or established acute phases
(∼14–19 d.p.i.) of the disease (Figure 1A). Samples are
sometimes available from vaccinated individuals with
undiagnosed immunodeficiencies but these are very
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M Ludlow et al
rare, meaning that much of what we know about the
pathological lesions in prodromal and early acute stages
comes from non-human primate infections [20–22]. A
major advance in understanding the early stages of the
disease was achieved when reverse-genetics systems
were developed for clinical isolates, which allowed the
generation of recombinant MVs expressing enhanced
green fluorescent protein (EGFP), which, in turn, per-
mitted the highly sensitive detection of infected cells
in vivo [23,24]. Cynomolgus macaques are the optimal
animal model for measles virus pathogenesis, as they
recapitulate many aspects of the disease in humans,
can be naturally infected and recover fully from the
infection [20,25]. Combining wild-type recombinant
(r) viruses, such as rMVIC323 EGFP (derived from a
Japanese wild-type MV) or rMVKS EGFP (derived from
a wild-type MV from Khartoum, Sudan), with this
macaque model has been instrumental in helping to
shed new light on MV pathogenesis and transmission
[23,26–28]. This is in direct contrast to what we learn
from human tissue samples, since the majority of these
are obtained post mortem, from individuals who have
either succumbed to other infections or have died
due to CNS complications, such as MIBE or SSPE
(Figure 1A). Secondary infections are prevalent during
measles because of the profound immune suppres-
sion which accompanies the disease (Figure 1A). For
example, bacterial pneumonitis and bronchiolitis are
frequently observed complications (see below). These,
in addition to underlying infections, such as HIV-1,
or malnutrition, make describing the pathological
consequences of the infection challenging.
Our previous reviews have been virocentric, concen-
trating on the molecular biology of MV and mutations in
the genome that occur when the virus reactivates months
to years after the primary infection [14,29,30]. In this
review we focus on virus cell entry, since dissecting
this step has been critical in understanding acute viral
pathogenesis and MV transmission. Given that measles
is predominantly a disease of the immune system, this
is where we start (Figures 1A, 1B, and 2). Recognizing
that as a respiratory pathogen the virus must be expelled
from the respiratory tract to ensure transmission, we
subsequently focus on how it crosses epithelial barriers
(Figures 1A, 1C, and 3). Finally, we address entry into,
and spread within, the CNS, the one aspect of pathogen-
esis which remains enigmatic (Figures 1A, 1D, and 4).
Entry and spread: systemic lymphotropism
The lymphotropic nature of MV is well recognized as
a distinguishing feature of the disease, with giant cell
formation reported in tonsils, appendix, lymph nodes,
thymus and spleen [31–34]. Understanding how MV
spreads with such specific cellular tropism through the
immune system is vital in pathogenesis studies. Identi-
fication of the cell surface receptor CD150 (SLAMF1),
which is expressed on activated immune cells, pro-
vided the key starting point [35]. The molecule is a
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Measles virus pathology 255

A progression

transmission

prodromal early acute established acute late

conjunctivitis ADME SSPE

coryza MIBE
Koplik’s spots

cough

rash

fever

secondary infections

immune suppression

immune
B

DCs macrophages B-cells T-cells

CD150 (activated immune cells)

C epithelia

simple columnar stratified squamous

PVRL4 (adherens junction)
D
neural
astrocvtes

neurons
oligodendrocytes

entry into CNS (?) and spread within CNS (?)

Figure 1. Summary of the clinical and pathological features of measles. (A) Temporal progression of measles clinical signs and disease
course. (B) Cellular tropism of MV in vivo is largely determined by the expression of the cellular receptors CD150 on subsets of immune
cells and PVRL4 on epithelial cells. The mechanism(s) of MV entry and spread in the CNS are undetermined.

member of the immunoglobulin (Ig) superfamily and is
expressed on subsets of B and T cells, dendritic cells,
macrophages, platelets and haematopoietic stem cells
[36,37]. It functions as a co-stimulatory molecule and
is involved in the regulation of innate and adaptive
immune responses [36,38]. The role of the C type lectin
DC-SIGN in measles pathogenesis is still uncertain.
Although this molecule is able to bind to and capture
Copyright © 2014 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
MV, it does not facilitate cell entry by mediating
virus-to-cell fusion at the plasma membrane, the normal
mode of morbillivirus entry into cells [39].
Early stages of infection have been examined
using viruses which express fluorescent proteins in
both macaque and transgenic mouse models [23,40].
Analysis of respiratory tract tissue from MV-infected
macaques shows that MV-infected dendritic cells
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256 M Ludlow et al

A DAPI/EGFP B

DAPI/CD11c/MV N

C DAPI/CYK/EGFP D EGFP E PI/EGFP

F EGFP G PI/EGFP H PI/EGFP

I DAPI/CYK/EGFP J DAPI/CD20/EGFP

Figure 2. MV-infection of the immune system of the macaque. MV-infected cells were detected directly in thin sections (A) and 200 μm
vibratome-cut sections (D–H) or indirectly by immunocytochemical (B inset, C, I, J) and immunohistochemical (B) staining. (A) Infection of
early target cells with the morphology of myeloid cells in the alveolar space; the walls of the alveoli are indicated with a dashed line. (B)
MV-infected cells in bronchial associated lymphoid tissue; (inset) MV-infected (green) CD11c+ myeloid cells (red) in the alveolar lumen of the
lung. (C) Syncytia (green) present in sub-epithelial lymphoid cells of the primary bronchus. (D) A syncytium of interconnected MV-infected
cells (green) in the tracheobronchial lymph node. (E) Individual and connected MV-infected immune cells in the tracheobronchial lymph
node. (F) Multiple MV-infected (green) B cell follicles in the spleen. (G) Higher-magnification image of B cell follicles in the spleen,
demonstrating specific targeting of these structures. (H) Dispersed MV-infected cells (green) in the spleen; (inset) at higher magnification,
connected cells are visible. (I) Aggregation of MV-infected immune cells (green) present beneath and within cytokeratin+ squamous
epithelium (red) of the tongue. (J) Infiltration of MV-infected (green) CD20+ B cells (red) into bronchial epithelium; the approximate
position of the bronchial lumen is indicated with a dashed line. Propidium iodide (red) was used as nuclear counterstain in plates (E, G, H);
DAPI was used in plates (A, B inset, C, I, J); square, B cells; triangle, T cells; diamond, dendritic cells; inverted triangle, macrophages.

and/or alveolar macrophages can be detected in the
lung as early as 2 (d.p.i.) (Figure 2A). Spread of
virus to bronchus associated lymphoid tissue (BALT)
(Figure 2B) and aggregates of CD11c+ myeloid cells
in alveolar spaces (Figure 2B, inset) results in local
amplification of virus infection between 3–5 d.p.i.
Following spread of the virus, giant cell formation is
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readily detected at the peak of infection (7–9 d.p.i.) in
bronchial lymphoid tissue (Figure 2C), and clusters of
MV-infected interconnected immune cells are present in
the trachea-bronchial lymph node (Figure 2D, E). Anal-
ysis of tissue sections from the spleen has shown that B
cell follicles are targets of MV infection (Figure 2F–G).
Scattered infected cells are also observed between
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Measles virus pathology
follicles (Figure 2H). Lymphoid depletion is observed
in these follicles following the peak of infection at 11
d.p.i. [28], a phenomenon which has also been noted
as a feature of measles in humans [31]. MV-infected
immune cells contact and/or infiltrate the epithelium at
the peak of infection [27,41], providing a mechanism
through which virus is seeded into both squamous
(Figure 2I) and columnar epithelia of the respiratory
tract (Figure 2J).
Morbilliviruses cause variable levels of immune
suppression, leading to increased susceptibility to
opportunistic infections [21,42], so that patients often
develop potentially life-threatening complications, such
as pneumonia or gastroenteritis [43–46]. Although
studied since the beginning of the twentieth century
[47], the relative importance of different mechanisms
leading to this immune suppression remains disputed.
Many studies have relied on in vitro observations,
making it very difficult to assess their importance for
immune suppression in vivo. Paradoxically, measles
is also associated with immune activation [48,49].
Patients develop robust MV-specific humoral and cel-
lular immune responses that mediate the clearance of
infected cells. Acute measles is associated with lym-
phopaenia, but peripheral blood lymphocyte numbers
normalize within days after resolution of the disease,
whereas immune suppression extends over a prolonged
period of time. This rapid recovery has been used to
argue against lymphocyte depletion as a direct cause
of measles immune suppression. Instead, research has
mainly focused on MV-mediated functional impair-
ment of lymphocytes and/or antigen-presenting cells
[50–52]. Following experimental MV infection of
non-human primates, the virus predominantly replicates
in memory T lymphocytes and follicular B lymphocytes
[28,53] (Figure 1B). Thus, infection and subsequent
depletion of CD150+ antigen-experienced lymphocyte
subsets may be considered as a potential mediator
of measles immune suppression [28]. Disappearance
of pre-existing memory lymphocytes is masked by
the rapid proliferation of newly induced MV-specific
lymphocytes, thus explaining the measles paradox.
Although infection of antigen-presenting cell popula-
tions and epithelial damage may contribute to the risk
of bacterial infection or dissemination during the acute
phase of the disease, long-term immune suppression
mainly results from depletion of pre-existing memory
lymphocyte populations [125].
MV lymphotropism: future perspectives
Although immune suppression and lifelong immunity
afforded by primary MV infection are both defining
features of measles, specific mechanisms leading to
immune system dysregulation remain controversial,
and our understanding of why MV stimulates such an
effective, long-lasting, immune response is still not
well integrated with our knowledge of virus tropism
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257
and pathological lesions. Further research using in vivo
models of measles may help to elucidate answers to the
following questions:
• Does MV binding to CD150 stimulate or block
CD150-mediated cell signalling pathways in immune
cells?
• Does MV vaccination provide lifelong immunity in
the absence of endemic virus transmission?
• Should vaccination cease if it is possible to eradicate
MV?
• Can a better understanding of the lifelong immunity
afforded by MV infection lead to more effective,
rational vaccine design for other pathogens?
Exit and transmission: local epitheliotropism
Textbooks traditionally suggested that epithelial cells
were the primary target for MV. However, as outlined
above, initial infection of immune system cells is essen-
tial for MV entry and systemic cell-to-cell spread. Given
that MV is a respiratory pathogen, this appears to be a
‘suicidal strategy’. The discovery of PVRL4 (nectin 4)
as the second natural MV receptor shows how elegantly
the virus has evolved to cross epithelial barriers and
ensure transmission to a susceptible host [54,55]. The
molecule is a component of adherens junctions, located
at the basolateral side of epithelia, and is a member of
the nectin family of adhesion molecules belonging to
the Ig superfamily [56]. Subsequent studies demonstrat-
ing usage of canine PVRL4 by canine distemper virus
(CDV) and ovine PVRL4 by peste des petits ruminant
virus confirmed that this molecule, like CD150, is also a
pan-morbillivirus receptor [57,58].
Focal areas of MV infection are present in multiple
epithelial tissues of the respiratory tract of MV-infected
macaques, including pseudostratified columnar epithe-
lial cells in the trachea (Figure 3A) and non-keratinized
stratified squamous epithelial cells in the tongue
(Figure 3B). We have also previously documented
infection of simple squamous epithelial cells in alveoli
and simple columnar epithelial cells in bronchi [26,53].
While much attention has been focused on MV-infected
cells in the trachea [41,55], it is clear that multiple
subtypes of epithelial cells are susceptible to MV infec-
tion, with different epithelia displaying various levels
of pathological lesions [26,27]. This is most evident in
the upper respiratory tract, where very large numbers
of contiguous epithelial cells in the nasal cavity are
infected [26–28]. Macroscopic screening shows these
are primarily in ciliated regions of the nasal mucosa
and that infection of the conchae is also pronounced.
These levels of infection probably explain the highly
transmissible nature of MV, and it is reasonable to
suggest that virus shedding from here, rather than
from the trachea, is important for host-to-host spread.
Syncytia of fused MV-infected cells are more readily
detected in columnar than in squamous epithelium, with
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258 M Ludlow et al

A EGFP B

D DAPI/CYK DAPI/MV N DAPI/CYK/MV N

E F DAPI/EGFP DAPI/EGFP

G DAPI/CD11c/MV N H DAPI/CYK/MV N

Figure 3. MV infection of macaque epithelial tissues. (A) MV-infected pseudostratified columnar epithelial cells in a 200 μm vibratome-cut
section of tracheal epithelium. (B–I) Immunocytochemically stained, microtome-cut epithelium tissue sections. (B) MV-infected stratified
squamous epithelial cells in the tongue. (C) Serial sections of primary bronchus; multinucleated giant cells (arrows) present in the epithelium
of an H&E-stained section (left) are positive for EGFP in a serial immunohistochemically stained section (right). (D) A large syncytium of
MV-infected cells in cytokeratin+ (CYK) pseudostratified columnar epithelial cells in the adenoid; single stains (left and middle panels), dual
label (right panel). (E) Exfoliation of a focus of MV-infected tracheal epithelial cells. (F) MV-infected epithelial cells (green) in the primary
bronchus undergoing exfoliation into the lumen; (right panel) higher magnification image of the boxed area. (G) CD11c+ myeloid cells (red)
are present beneath and within (arrows) MV-infected (green) bronchial epithelium. (H) Extensive disruption and dissolution of adenoidal
epithelium due to infiltration of MV-infected immune cells (green; arrows); MV-infected cytokeratin+ pseudostratified columnar epithelial
cells (green and red) are indicated by arrowheads. Propidium iodide (red) was used as nuclear counterstain in (A); DAPI in (D, F–H); triangle,
columnar; diamond, stratified squamous.

syncytia containing >30 nuclei readily detected in both
bronchial and adenoidal epithelium (Figure 3C, D).
Exfoliation of MV-infected columnar epithelial cells
into the lumen of the respiratory tract is also observed in
both the trachea and the bronchus (Figure 3E, F). This
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pathological response may serve as one mechanism
through which virus is released into the environment
following the induction of a cough response. We have
also observed extensive pathological lesions in the
respiratory epithelium in the latter stages of the disease
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Measles virus pathology
(9–11 d.p.i.), with dissolution of epithelium observed
in the bronchus (Figure 3G) and more extensively
in lymphoid tissues, such as adenoidal (Figure 3H)
or tonsillar tissue [26]. Such MV-infected epithelia
are extensively infiltrated by immune cells, resulting
in disruption of epithelial integrity, which may con-
tribute to the cell-free and cell-associated virus we have
detected in throat brushings and nasal swabs from these
animals [26].
How the interaction of the MV H glycoprotein with
PVRL4 might perturb the normal functioning of this
molecule in adult epithelial tissues remains a topic for
future investigation. PVRL4 has been shown to interact
with both PVRL1 via its extracellular V domain, and
with afadin via its cytoplasmic domain sequence [56].
Afadin is an F-actin-associated molecule that connects
the actin cytoskeleton to the nectin complex at the
adherens junction [59,60]. Although fetal tissue and
adult placental tissue show high levels of PVRL4, only
low levels of expression are found in other adult tissues,
including the trachea, lung and stomach [56,61,62].
There have also been a number of reports investigat-
ing the efficacy of PVRL4 as a diagnostic marker
for breast, lung and ovarian cancer [62–65] and a
recent study has shown that up-regulation of PVRL4
promotes anchorage-independent growth of tumour
cells [66].
MV epitheliotropism: future perspectives
While much progress has been made in understanding
how the MV H glycoprotein interacts with PVRL4 from
a molecular perspective [67,68], many aspects of the
pathological consequences of this interaction in vivo
with respect to MV cell-to-cell spread and transmission
remain to be determined, including:
• What is the distribution, spatial organization and
expression level of PVRL4 in human tissues?
• Is it possible for MV to disrupt the integrity of the
epithelium by interacting with PVRL4 without infect-
ing epithelial cells?
• Do innate immune responses in infected epithelial
cells contribute to the pathological lesions observed
within epithelia?
Acute and persistent: extreme neurotropism
Most cases of measles resolve without neurological
sequelae following systemic virus spread. However,
studies of brain tissue obtained from autopsy sub-
jects report the presence of MV mRNA in approxi-
mately 20% [69,70] and transient electroencephalogram
changes have been observed in children with uncompli-
cated measles [71]. It remains to be determined whether
these observations support the persistence of MV within
the CNS in the absence of clinical disease, but three
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259
well-delineated and distinct neurological complications
have been described (reviewed in [72,73]).
Acute demyelinating encephalomyelitis (ADME) is
a neurological complication which typically occurs in
children or young adults following a viral or bacte-
rial infection [74]. A number of pathogens have been
associated with ADME, including Epstein-Barr virus,
herpes simplex virus, influenza virus and Mycoplasma
pneumonia [75,76]. A diagnosis of ADME has also
been reported in approximately 1 of 1000 measles
cases following the systemic phase of the disease
[77]. The pathogenesis of ADME is poorly understood
but is thought to have an autoimmune component,
as myelin basic protein (MBP) can be detected in
cerebrospinal fluid in ADME patients, together with
lymphocyte-proliferative responses against MBP [78].
Very few studies have reported direct evidence of MV
infection, such as viral RNA or antigen in CSF or brain
biopsies from ADME patients [79]. While many aspects
of ADME pathogenesis are unknown, perivenous infil-
tration with perivascular demyelination and associated
white matter lesions have been described [77].
Measles inclusion body encephalitis (MIBE) typ-
ically occurs in immunocompromised individuals
within 1 year after resolution of uncomplicated measles
[80,81]. The condition has been reported in children
with leukaemia or transplant patients undergoing an
immunosuppressive therapy regime and in children
co-infected with human immunodeficiency disease
virus (HIV)-1 [82–84]. Few detailed pathological
descriptions of MIBE have been reported but infection
of neurons and glial cells has been observed in brain
tissue from MIBE patients [85,86].
The term ‘subacute sclerosing panencephalitis’
(SSPE) was first used in 1950 to describe a ‘sporad-
ically occurring European encephalitis’ [87]. It is a
disease that develops in children 5–10 years after a nor-
mal episode of natural measles, despite the presence of
MV-specific antibody titres [88], and is a paradigm for
the long-term persistence of an RNA virus in humans.
In rare cases, prolonged persistence of MV may lead
to the development of SSPE in immunocompetent
adults, including a 49 year-old man who had measles
at the age of 2 [89]. Clinically, this inevitably fatal
disease is characterized initially by subtle behavioural
changes, which lead progressively over a period of
1–3 years to myoclonic jerks, ataxia and death, which
in many cases is due to pneumonia [90–92]. In some
cases a more rapid fulminant disease course has been
observed, particularly in adults [93,94]. The frequency
of SSPE has been re-evaluated in recent years, as the
reduction in overall numbers of measles cases following
the introduction of an efficacious vaccine has made
it easier to compare the number of SSPE cases to the
‘true’ number of measles infections [95]. SSPE cases
have been reported at a rate of approximately 1:10
000 natural measles infections in some subdistricts
of Papua New Guinea [96,97], 1:4635 in the USA
[95] and as high as 1:1700–1:3300 for children in
Germany [98].
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260
A viral aetiology for SSPE was first suggested follow-
ing the observation of intracytoplasmic and intranuclear
inclusion bodies in two cases of what was then termed
‘lethargic or epidemic encephalitis’ [99,100]. Later,
viral particles characterized as paramyxovirus in origin
were detected by electron microscopy in brain biopsies
taken from SSPE patients [101]. Direct confirma-
tion that MV was pathologically linked to SSPE was
obtained using MV-specific antisera to detect infected
neurons and glial cells in brain sections [88]. The
pathology of SSPE is determined by a complex mixture
of the unique neuronal environment, host genetics and
the trans-synaptic spread of mutant variants of MV.
Direct sequencing of MV from SSPE brain tissue has
shown that viruses contain a multitude of mutations,
leading to an absence of M protein in infected cells
and expression of F glycoproteins with truncated cyto-
plasmic tails [102–105]. For further information on the
genetic variation displayed by ‘SSPE viruses’, we refer
readers to previous reviews we have published on this
subject [14,29].
Pathologically, the brains of SSPE patients are char-
acterized by inflammatory infiltrates in both the grey
and white matter, explaining the term ‘panencephalitis’.
Diffuse demyelination, astroglial sclerosis and viral
antigen-containing inclusion bodies in neurons and
oligodendrocytes are also observed [106]. While the
neurological aspects of SSPE are well characterized, it
is still unknown where MV ‘persists’ in the body prior
to the onset of overt clinical signs. Reports of MV RNA
and/or antigen in peripheral lymphoid tissues of SSPE
patients are sparse [107–109] and thus must be treated
with caution. Similarly, the route of entry of MV into the
CNS is also unknown, but is assumed to occur via anal-
ogous mechanism(s) to CDV in members of the family
Canidae. Although MV infection has been reported in
limited numbers of human cerebral endothelial cells and
larger numbers of cells in perivascular cuffs in SSPE
brain tissue [110,111], studies have been limited by the
fact that biopsy and/or brains from SSPE patients are
only available after the onset of neurological clinical
signs. The role of CD150 and PVRL4 in mediating the
entry and/or cell-to-cell spread of MV within the CNS
is unknown. One study has reported CD150 expression
in subsets of leukocytes in inflammatory infiltrates, but
found that expression was absent in the rest of the brain
parenchyma [112].
MV infection of neurons in the human CNS
Detailed pathological and ultrastructural studies of
SSPE brain tissue have indicated that the mechanism of
viral spread in the CNS is different from that observed
in non-neuronal cells. Examination of brain tissue
from patients with MIBE and SSPE has shown that the
presence of MV antigen in neurons is a characteristic
feature [113,114]. The close proximity of MV-infected
interconnected neurons in the absence of syncytium
Copyright © 2014 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
M Ludlow et al
formation suggests that a novel mechanism of viral
transmission may mediate the spread of MV from
neuron-to-neuron. We have also observed numerous
MV-infected neurons with extended dendritic processes
in immunostained brain sections from the temporal lobe
of an SSPE case (Figure 4A, 4B) and the frontal cortex
of an MIBE case (Figure 4D, 4E). No co-localization
was observed in the grey matter of an SSPE patient
between MV antigen present in neuronal tracts and
NOGO, a marker for oligodendrocytes (Figure 4C).
While cell-to-cell transmission of nucleocapsids was
first suggested as a possible mechanism for the spread of
MV in the brains of SSPE patients 40 years ago [115],
the specific mechanism(s) responsible for mediating
spread across the synapse is still unknown. However,
the recent report of a reverse-genetics system for an
‘SSPE virus’ could re-energize studies into neurological
aspects of MV infections [116].
MV infection of glial cells in the human CNS
Although the presence of MV antigens in oligodendro-
cytes is a characteristic feature of SSPE, the extent of
astrocyte cell infection in SSPE remains controversial,
as previous studies have reported the presence of MV N
protein in varying numbers of astrocytes [113,117,118].
We have observed abundant MV-positive cells with
the morphological appearance of oligodendrocytes, but
only limited numbers of infected astrocytes in the white
matter of SSPE cases (Figure 4F). Examination of white
matter areas on adjacent sections with triple-labelling
immunofluorescence revealed abundant GFAP-positive
astrocytes and CD68-positive foamy macrophages.
However, MV-positive cells with the smaller, more
rounded morphology of oligodendrocytes were dis-
tinct from these two cell populations (Figure 4G–I).
Dual-labelling immunofluorescence staining with
anti-NOGO antibody confirmed that MV-infected
oligodendrocytes are also present in MIBE brain tissue
(Figure 4J, 4K). It is assumed that virus spread in glial
cells occurs via interconnected cellular processes as
MV-induced fusion between neighbouring glial cells
has been observed in both a case of SSPE and a case of
MIBE [119,120].
MV neurotropism: future perspectives
Since MV was first isolated from brain biopsies obtained
from SSPE patients over 30 years ago, comparatively
little progress has been made in delineating the patho-
genesis of this severe neurological disease. A number of
questions remain to be elucidated:
• What is the specific mechanism(s) mediating
trans-synaptic MV spread?
• How is the MV ribonucleoprotein transported along
axons?
J Pathol 2015; 235: 253–265
www.thejournalofpathology.com
Measles virus pathology 261

A B PI/MV N

C SSPE/NOGO/NFP D PI/MV N E PI/MV N

F PI/MV N G GFAP/MV N H GFAP/CD68/SSPE

I SSPE/CD68/GFAP J SSPE/NOGO/GFAP K SSPE/NOGO/GFAP

Figure 4. MV-infection of the human central nervous system. Detection of MV-infected cells in MIBE (A–C, I–K) and SSPE (D–H) human
brain tissue sections. MV antigen was detected by immunohistochemical (A) or immunocytochemical (B–K) staining. (A) Individual
MV-infected cortical neurons are observed in the grey matter. (B) Three MV-infected neurons in the grey matter are surrounded by multiple
infected neuronal processes. (C) MV antigen (blue) is associated with neuronal tracts (green) in the cortex, with no virus spread observed
to NOGO+ oligodendrocytes (red). (D) Detection of MV antigen (green) in neurons of the frontal cortex by tyramide signal amplification;
cytoplasmic inclusions of MV N protein are present in a neuronal cell body (arrow) and in a number of neuronal processes (arrowhead). (E)
A characteristic ‘beading’ pattern of aggregations of MV antigen is observed along dendritic processes of individual neurons. (F) Detection
of MV antigen (yellow) in oligodendrocytes in the white matter by tyramide signal amplification. (G) MV antigen (green) is restricted to
oligodendrocytes in the white matter; no dual labelling is observed with GFAP+ astrocytes (red) or CD68+ foamy macrophages (red). (H) No
virus spread is observed from MV-infected oligodendrocytes (green) in the white matter to adjacent to CD68+ foamy macrophages (red) or
GFAP+ astrocytes (blue). (I) MV-infection (blue) is restricted to oligodendrocytes in the white matter, with no dual labelling observed with
either CD68+ macrophages (red) or GFAP+ astrocytes. (J) MV-infected (blue) NOGO+ oligodendrocytes (red) are present in the white matter.
(K) No virus spread is observed from MV-infected white matter oligodendrocytes (blue and red) to GFAP+ astrocytes (green). Propidium
iodide (red) was used as nuclear counterstain in (B, D–F); square, neurons; diamond, oligodendrocytes.

• Where are the intracellular sites of MV RNA synthesis Conclusions

in neurons?
• How does the presence of large foreign RNA/protein
aggregates interfere with the normal functioning of
neurons?
Copyright © 2014 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
Collaborative, multidisciplinary research combining
molecular virology, cell and tissue imaging, animal
models of disease and targeted pathology have radically
J Pathol 2015; 235: 253–265
www.thejournalofpathology.com
262
changed our understanding of measles pathogenesis.
These recent advances, alongside the availability of a
highly efficacious vaccine, make MV a perfect platform
for comparative studies. Understanding the molecular
basis of attenuation, and dissecting how a vaccine virus
behaves in vivo compared to the wild-type progenitor,
are important. Efforts are being made to move away
from the standard, empirical approach to live attenuated
vaccine development, in which a clinical isolate is
repeatedly passaged in inappropriate cells. Molecular
approaches in which targeted modifications are made
to viruses based on a comprehensive understanding
of the mechanisms of attenuation are attractive, given
the challenges in licensing new vaccines and the need
to ensure vaccine safety. Since measles vaccination
leads to lifelong immunity, efforts should be made to
understand the mechanisms of attenuation and assess
whether this knowledge can be used for other viruses. At
present we do not know the initial target cells of the MV
vaccine, whether or not it uses non-natural receptors
in vivo [121,122] or how long the virus persists follow-
ing the injection of vaccinees. Such basic knowledge
is essential and is directly applicable to other live
attenuated vaccines, such as mumps and rubella. Tar-
geted pathology helps to answer these questions and
the approaches developed to understand the systemic
disease are directly applicable to vaccine viruses. Given
the genetic stability of MV and its ability to retain extra
genes in vivo, it is an ideal platform for the delivery
of antigens from other pathogens [123,124]. Serious
thought needs to be given to the issues surrounding
continued vaccination in a post-MV-eradication world.
Issues such as morbillivirus emergence from animals
or, less likely but nevertheless possible, the use of the
virus as a bioweapon, cannot be ignored. Both should be
considered, as it is challenging to maintain vaccination
rates in developed countries when endemic transmission
is stopped. In a post-eradication world it is very likely
that significant numbers of people would opt out of
routine MV vaccination. Are these issues threats or
opportunities? It could be argued that now is the perfect
time to invest in understanding both the disease and vac-
cine to inform our thinking. Further research is required
in order to understand transmission, the longevity of
immune suppression and the interplay between CD150
and PVRL4. This will require strong pathological foun-
dations and appreciation of the complex lymphotropic,
epitheliotropic and neurotropic nature of MV.
Acknowledgements
We wish to thank Ingrid Allen, Ken Lemon and Bert
Rima (Queen’s University of Belfast, Northern Ire-
land, UK) and Rory de Vries and Albert Osterhaus
(Erasmus MC, Rotterdam, The Netherlands) for helpful
discussions and support. We acknowledge Geert van
Amerongen (Erasmus MC), who provided unparalleled
zootechnical skills, and the staff of the Tissue Core
Copyright © 2014 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
M Ludlow et al
Technology Unit (Queen’s University of Belfast) for
their histological expertise. This work was funded
by the Medical Research Council (MRC; Grant No.
G0801001) and by ZonMw (Grant No. 91208012) to
WPD and RdS, respectively. The funders had no role in
study design, data collection and analysis or decision to
publish, or in the preparation of the manuscript.
Author contributions
WPD and RdS conceived and designed the experiments;
WPD, RdS, ML and SMcQ performed the experiments
and analysed the data; and DM provided pathological
oversight and commented on existing data; all authors
were involved in writing the paper; WPD and ML assem-
bled the figures; and all authors approved the submitted
and published versions.
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