Available online at www.sciencedirect.
com
ScienceDirect
Measles pathogenesis, immune suppression and animal
models
Brigitta M Laksono1, Rory D de Vries1, W Paul Duprex2,3 and
Rik L de Swart1
Measles virus causes a disease with seemingly innocent
symptoms, such as fever and rash. However, measles immune
suppression causes increased susceptibility to opportunistic
infections that are responsible for the majority of over
100 000 yearly fatalities. The pathogenesis of measles is
complex, because measles virus uses multiple receptors to
infect different cell types in different phases of the disease.
Experimental morbillivirus infections with wild-type viruses in
natural host species have demonstrated that direct infection
and depletion of memory immune cells causes immune
amnesia. This was confirmed in studies of a measles outbreak
in unvaccinated children and provides an explanation for
epidemiological observations of long-term increases in
morbidity and mortality after measles.
Addresses
1
Department of Viroscience, Erasmus MC, Dr. Molewaterplein 40,
3015 GD Rotterdam, The Netherlands
2
Centre for Vaccine Research, University of Pittsburgh School of
Medicine, 3501 Fifth Avenue, Pittsburgh, PA15261, United States
3
Department of Microbiology and Molecular Genetics, University of
Pittsburgh School of Medicine, 3501 Fifth Avenue, Pittsburgh, PA15261,
United States
Corresponding author: de Swart, Rik L (r.deswart@erasmusmc.nl)
Current Opinion in Virology 2020, 41:31–37
This review comes from a themed issue on Special section: measles
Edited by Rik L de Swart and Makoto Takeda
For a complete overview see the Issue and the Editorial
Available online 24th April 2020
https://doi.org/10.1016/j.coviro.2020.03.002
1879-6257/ã 2020 Elsevier B.V. All rights reserved.
Introduction
Measles virus (MV) is the prototypic member of the
genus Morbillivirus, family Paramyxoviridae [1], and
causes measles in humans and non-human primates
(NHPs). In humans, the disease generally occurs during
childhood and presents after a relatively long incubation
period. The first signs appear around ten days after
infection, as fever and cough develop and the patient
becomes highly contagious. At this point, ulcerated white
lesions, known as the pathognomonic Koplik’s spots,
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appear on the buccal mucosa. The symptomatic phase
follows a few days later with the appearance of an ery-
thematous, morbilliform skin rash. A robust, virus-specific
immune response is induced during this phase, which
leads to viral clearance, recovery from symptoms and
lifelong immunity to measles. Measles also paradoxically
induces a transient immune suppression, which leads to
increased levels of morbidity and mortality up to several
years after recovery [2,3]. The course of measles is
illustrated in Figure 1. MV remains a major global health
threats to humans, causing more than 140 000 deaths in
2018 [4].
To study the pathogenesis of measles, it is crucial to
understand the interaction between MV and its target
cells. MV infects cells by releasing its encapsidated
negative-sensed genome into the host cell after recep-
tor-dependent virus-to-cell membrane fusion [5]. CD150
(also known as signalling lymphocyte activation mole-
cule family member 1 or SLAMF1) and nectin-4 (also
known as poliovirus receptor related-4 or PVRL-4) are
the cellular receptors of wild-type MV, which explain
virus lymphotropism and epitheliotropism, respectively
[6,7,8,9]. CD150 is expressed by several subsets of
immune cells, including macrophages, dendritic cells
(DCs) and lymphocytes. Nectin-4 is a part of the adhe-
rens junction complex and expressed on the basolateral
side of polarised epithelial cells. Nectin-4 is also
expressed by endothelial cells and keratinocytes
[10,11]. Although the first MV cellular receptor discov-
ered was CD46, a cell surface molecule ubiquitously
expressed by most nucleated cells, subsequent studies
showed that the CD46-mediated entry is limited to
vaccine and laboratory-adapted MV strains [12,13]. In
addition to these formal entry receptors, MV can also
attach to binding receptors, such as the C-type lectins
DC-specific intercellular adhesion molecule-3-grabbing
non-integrin (DC-SIGN) and Langerin, which are
expressed on DCs and Langerhans cells, respectively.
Capture of MV particles by these molecules leads to
CD150-mediated infection of DCs (in cis) or lympho-
cytes (in trans) [14,15]. The ability of MV to infect
different, highly motile cells in various anatomical com-
partments, such as the respiratory tract, lymphoid tissues,
gastrointestinal tract and skin, complicates the study of
measles pathogenesis. This review features an integrated
perspective on the current studies of pathogenesis of
measles and measles-associated immune suppression.
Current Opinion in Virology 2020, 41:31–37
32 Measles

Figure 1

Pathogenesis of measles
Infection of local Systemic Immune
Entry Prodromal Symptomatic Recovery
lymphnodes dissemination suppression

O. Composition of lymphocyte population before and after measles

Newly expanded lympocytes

Pre-existing CD150+
MV-specific lymphocytes
lymphocytes

Pre-existing CD150-
lymphocytes

P.Type of cells infected by MV over time

Non-ciliated Ciliated
DC Macrophage Lymphocyte Keratinocyte MV RNP
epithelial cell epithelial cell

Current Opinion in Virology

The pathogenesis of measles. Schematic representation of the course of MV infection. The green bell-shaped curve in the background of the top
panel represents the viral load over time. MV enters the upper (a) or lower respiratory tract (b) by infecting CD150+ or binding to DC-SIGN+
dendritic cells (DCs) or alveolar macrophages. These infected cells migrate to bronchus-associated lymphoid tissues (c) or draining lymph nodes
(d) to spread the infection further to susceptible lymphocytes. MV-infected CD150+ lymphocytes, mostly CD4+ memory T cells, disseminate the

Current Opinion in Virology 2020, 41:31–37 www.sciencedirect.com

 Measles pathogenesis, immune suppression and animal models Laksono et al. 33

Animal models andpathologicaloutcomestothoseinhumansandthus have

Mice are not naturally susceptible to MV infection,
necessitating the development of transgenic mouse mod-
els to study measles pathogenesis. However, most of
these mice are receptor knock-in animals deficient in
type I interferon signalling to facilitate wild-type MV
infection and replication. Thus, data obtained from these
models should be interpreted cautiously. Infections with
closely related animal morbilliviruses can be studied in
their natural hosts as an alternative, for example canine
distemper virus (CDV) is a useful surrogate to study the
pathogenesis of MV infections. CDV infects a broad
range of hosts, such as dogs, raccoons and ferrets
[16,17]. Among these hosts, ferrets (Mustela putorius furo)
can be handled in a laboratory environment and have a
respiratory tract similar to humans. Recombinant CDV
(rCDV) strains expressing a fluorescent reporter protein
have been used in ferret models, allowing sensitive
detection of infected cells and tissues and determination
of morbilliviral tropism in its natural host [16]. Lastly, the
use of ferrets as an animal model for other viral diseases
has also been established and, although limited, reagents
and tools are available [18]. Despite these advantages,
wild-type CDV in ferrets is not an ideal mimic of MV
infection in primates, since CDV infection in ferrets
typically results in faster disease progression, neurologi-
cal complications and high mortality rates, while MV
infection in primates rarely results in neurological com-
plications or death.
The current knowledge regarding the pathogenesis of
measles thus owes much to in vivo studies in non-human
primates (NHPs), which are naturally susceptible to MV
infection. They are the ideal animal model to study measles
pathogenesis. MV infection of New World monkeys can
lead to severe or even lethal outcomes, deeming them
unsuitable as animal model [19,20]. However, in a recent
study squirrel monkeys (Saimiri sciureus), a New World
species, closely reproduced clinical symptoms of measles
in humans [21]. Unfortunately, this model is still limited by
the lack of cross-reactive reagents. Rhesus (Macaca mulatta)
and cynomolgus macaques (Macaca fascicularis) present
similar clinical symptoms and virological, immunological
been commonly used as an animal model for measles [22].
Despite the similarities, the two macaque species still differ
in their clinical presentation. Rhesus macaques have been
reported to develop more distinct skin rash and conjuncti-
vitis than cynomolgus macaques [22–24]. The use of NHPs
as laboratory animals also raises ethical concerns and is
progressively more strictly regulated. Nonetheless, the
availability of cross-reactive reagents makes macaques
the ideal animal for in vivo measles studies. Furthermore,
the use of recombinant MVs (rMVs) based on wild-type
strains expressing a fluorescent reporter protein allows the
thorough observation of viral tropism, disease kinetics and
pathogenesis. Altogether, a good animal model for measles
requires the right selection of virus, the susceptibility of the
host and the availability of tools and methods to follow the
course of the disease.
MV entry
The highly infectious MV is transmitted by aerosols and
small droplets. Respiratory epithelial cells are not the
initial targets of the virus, because nectin-4 is only
expressed at the basolateral side [25]. Inoculation of
NHPs with wild-type rMV expressing enhanced green
fluorescent protein showed that myeloid cells in the
respiratory submucosa and the lungs are the initial
target cells in an MV infection, suggesting that MV
infection starts by infection of CD150+ alveolar macro-
phages or the binding to DC-SIGN+ submucosal DCs in
the lumen of the respiratory tract (Figure 1a,b) [26–30].
An alternative route of entry is via the conjunctiva,
which contains susceptible CD150+ myeloid and lym-
phoid cells. Eye protection during contact with measles
patients reduces the risk of MV infection, suggesting
that, although to a lesser degree, MV can use the ocular
route to enter the host [31]. Simultaneous intranasal,
intratracheal and ocular administration of rCDV expres-
sing different fluorescent reporter proteins to ferrets
resulted in multicolour viremia, showing that morbilli-
viruses are able to enter the host at different anatomical
locations, as long as susceptible myeloid or lymphoid
cells are accessible [32].

infection systemically either through the circulatory system (e) or the lymphatic system (f). Infection of respiratory epithelial cells from the
basolateral side, combined with epithelial damage, leads to the release of infectious MV particles into the lumen of the respiratory tract
(g). Infection of dermal myeloid and lymphoid cells is followed by the spread of the infection among epidermal keratinocytes in a nectin-4-
dependent manner (h). MV-specific lymphocytes start to expand to clear the infection (i). Hyperaemia of the skin capillaries leads to the
recruitment of MV-specific lymphocytes and activated macrophages to infected skin areas and, together with oedema, gives the appearance of
erythematous, morbilliform skin rash (j). Upon recovery, loss of lymphocytes is partly masked by the expansion of newly generated cells (k). Skin
rash disappears and the epidermis is cleared of infection (l). The patient is protected against clinical measles for life. However, due to the loss of
pre-existing lymphocytes and plasma cells (m) and, consequently, pre-existing antibodies (n), the patient becomes susceptible to other infectious
diseases, especially respiratory infectious diseases. (o) The schematic representation of lymphopenia and changes in the composition of
lymphocyte populations before and after measles. The lymphotropic nature of MV leads to the infection and depletion of CD150+ pre-existing
lymphocytes, but the long-term loss is masked by the rapid generation of MV-specific cells and the expansion of new cells due to homeostatic
responses. (p) The types of cells infected by MV over time. Myeloid cells act as initial target cells and ‘Trojan horses’ by transporting virus to
CD150+ cells in lymphoid tissues. Lymphocytes play a major role in systemic dissemination, while respiratory epithelial cells are crucial in viral
transmission. The dermal myeloid and lymphoid cells and the epidermal keratinocytes are responsible for the appearance of skin rash. MV-
infected cells are mostly cleared by MV-specific immune cells but some lymphocytes still harbour MV RNA long after recovery from measles.

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34 Measles
Local and systemic dissemination of MV
MV infection spreads as infected cells migrate to bron-
chus-associated lymphoid tissues or draining lymph nodes
(Figure 1c,d) [29,33]. In addition to migrating MV-
infected cells, MV can be carried by DC-SIGN+ DCs
and use these cells as a ‘Trojan horse’ to disseminate the
virus systemically. Through cell-to-cell interaction, MV
spreads to susceptible CD150+ lymphocytes in the tissue-
associated lymphoid tissues. CD150 is abundantly
expressed in T cells, with higher expression in memory
cells than in the naive cells. In B cells, the dichotomy is
less prominent, since both naive and memory cells
express high levels of CD150. As a consequence, memory
T cells and naive and memory B cells are predominant
target cells for MV infection in the lymphoid tissues
[34,35,36]. The large number and the close interaction
of susceptible myeloid and lymphoid cells in the draining
lymph nodes allow rapid dissemination throughout the
tissues [29]. Newly MV-infected lymphocytes subse-
quently leave the tissues and disseminate systemically,
leading to a cell-associated viremia (Figure 1e,f), and
spread the infection to other tissues and organs, such
as peripheral lymph nodes, thymus, bone marrow, spleen,
gastrointestinal tract, kidney, liver and skin. The mobility
of MV-infected cells, the accessibility of organs to those
cells and the availability of susceptible cells in different
organs are important factors during the systemic dissemi-
nation of MV.
Prodromal phase of measles
During systemic dissemination, early acute measles
patients exhibit coughing and fever, sometimes accom-
panied by diarrhoea and/or vomiting and conjunctivitis,
and become lymphopenic. Patients are highly contagious
during the prodrome, and infectious virus can be isolated
from throat and nose swabs, with higher virus titres found
in the nose than in the throat [36]. Respiratory epithelial
cells become infected at this stage, through contact
between MV-infected lymphoid or myeloid cells in the
respiratory submucosa and nectin-4 on the basolateral
side of these epithelial cells (Figure 1g). MV ribonucleo-
protein (RNP) genomic complexes can be trafficked
laterally in the respiratory epithelium through F-actin
rings, demonstrating direct cell-to-cell transmission of
MV [37,38]. MV infection of the epithelial cells subse-
quently leads to the production of new virus particles at
the apical cell surface. The new virus particles are then
released into the mucus that lines the lumen of the
respiratory tract. Simultaneously, epithelial damage in
the bronchi and bronchioles induces coughing. Combined
with the lack of nectin-4 expression at the luminal surface
of epithelial cells, this results in unimpeded expel of
infectious virions in large droplets or small aerosols
(Figure 1g) [33,39].
Symptomatic phase of measles
The emergence of skin rash marks the beginning of
clinical measles. MV-infected myeloid and lymphoid
Current Opinion in Virology 2020, 41:31–37
cells enter the dermis through the circulation. Here they
interact with skin-resident myeloid and lymphoid cells in
the dermal papillae or near hair follicles or sebaceous
glands, where blood vessels and capillaries are abundantly
present (Figure 1h) [26,40,41]. Infection in the dermis is
disseminated to the keratinocytes in the epidermis and
the virus spreads apically and laterally in a nectin-4-
dependent manner [42]. In experimentally infected
NHPs, MV-infected cells were present in the dermis at
the peak of viremia (9 days post-inoculation) and the
infection continued to spread to the epidermis the fol-
lowing days [42]. At this time point, MV-specific IgM
antibodies can be detected, demonstrating expansion of
MV-specific lymphocytes (Figure 1i) [43]. Maculopapular
skin rash appears around 11 days post-inoculation, during
which inflammatory responses and mononuclear cell infil-
tration are detected in the dermis and epidermis
(Figure 1j) [42]. The appearance of the erythematous,
morbilliform skin rash possibly originates from the
appearance of oedema and hyperaemia as a response to
MV infection of the skin [42]. The importance of the host
immune response in the pathogenesis of measles skin
rash is demonstrated by the absence of skin rash in
immunocompromised patients [44].
Recovery phase of measles
The majority of MV-infected cells either die due to
infection or are cleared by MV-specific CD8+ T cells
[45,46]. New lymphocytes, either MV-specific or freshly
recruited from the bone marrow, soon become available in
lymphoid tissues and peripheral blood and the number of
lymphocytes recovers to normal level (Figure 1k). During
recovery, new epithelial cells and keratinocytes proliferate
and differentiate to make up losses (Figure 1l). Although
recovery is often without complications, rare but severe
measles-associated central nervous system (CNS) compli-
cations may occur: acute disseminated encephalomyelitis
(ADEM), measles inclusion body encephalitis (MIBE) or
subacute sclerosing panencephalitis (SSPE). ADEM hap-
pens during the recovery phase and is immune-mediated,
possibly caused by molecular mimicry based on similar
structure between MV proteins and myelin [47]. MIBE
occurs in young infants or immunocompromised patients
after several days or months after acute measles or vacci-
nation [48]. SSPE, unlike other measles-related CNS
complications, is exclusively caused by wild-type MV
infection [49]. How MV spreads to and in the CNS
remains unknown, although recent studies have shown
that hyperfusogenic viral complexes can mediate CD150-
independent and nectin-4-independent viral entry. This
hyperfusogenicity is caused by amino acid substitutions in
the ectodomain of the MV fusion (F) glycoprotein, which
are reported in SSPE and MIBE cases [50,51,52]. Another
recent study also describes the transfer of cytoplasmic
cargo, including infectious materials, from cell to cell
through nectin-1-nectin-4 interaction. Consequently,
nectin-4+ epithelial cells can transfer infectious MV
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 Measles pathogenesis, immune suppression and animal models Laksono et al. 35
RNP to nectin-1+ primary neurons [53]. To date, there is
no treatment for measles-associated CNS complications
and hence MV infection in the CNS will ultimately result
in death.
MV genomic RNA has been reported to persist in experi-
mentally infected NHPs up to 50 days post-inoculation in
peripheral blood mononuclear cells (PBMC) and 71 days
post-inoculation in lymph nodes. The decline of the RNA
in blood occurred in three phases: a rapid decline due to
clearance of infected cells (10–14 days post-inoculation),
a transient increase up to 10-fold (14–24 days post-
inoculation) and a slow decrease to undetectable levels
(24 days or more after inoculation). This indicates that MV
might persist in the host for much longer than generally
recognised [54,55]. Persistence of MV RNA has also been
reported in naturally MV-infected Zambian children up to
four months after the onset of skin rash [56].
Measles-associated immune suppression
Several mechanisms have been proposed to explain mea-
sles-associated immune suppression, such as suppression
of lymphocyte proliferation, altered cytokine profiles,
apoptosis of bystander lymphocytes, and infection and
depletion of pre-existing CD150+ DCs and lymphocytes
[57]. On the basis of the preferential MV infection of
memory lymphocytes in experimentally infected NHPs,
we proposed immune amnesia as a mechanism of measles-
associated immune suppression [34]. This tropism was
confirmed in PBMC collected from early acute measles
patients. Moreover, in paired PBMC samples collected
from unvaccinated children before and after measles there
was a significant reduction in the percentages of circulat-
ing memory T and B cell subsets [36]. This reduction was
detectable more than a month after recovery. Simulta-
neously, MV infection led to the loss of pre-existing
antibodies in the plasma isolated from the same paired
samples, most likely due to MV infection and depletion of
plasma cells in the bone marrow [58]. Accordingly, B cell
receptor sequencing of the memory B cell pool from the
paired PBMC samples showed reduction of pre-existing B
cell memory clones, which were not reconstituted after
measles [59]. The combined loss of memory T and B cells
and, ultimately, pre-existing antibodies through the loss
of long-lived plasma cells, causes immune amnesia
(Figure 1m,n). Children are more likely to suffer from
non-measles infectious diseases, especially upper respira-
tory infections, which may last several years after recovery
from measles [2,3].
The significant reductions in the frequency of some
circulating lymphocyte subsets after measles is accompa-
nied by increased frequencies of others. The most inter-
esting subsets that increase in relative size after measles
are transitional B cells, which are bone marrow emigrants
with reduced proliferation capacity, and regulatory T cells,
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which are responsible for suppression of T cell responses
after immune activation [36,60]. B cell receptor sequenc-
ing of naive B cells from the paired PBMC samples
revealed incomplete recovery of the genetic composition
of naive B cells with signatures of immunological imma-
turity, consistent with the observed influx of transitional B
cells in these paired samples [59]. The masking effect by
newly generated cells, such as transitional B cells and
regulatory T cells, complicates the observation of measles-
associated immune suppression, since there is no clear
discrimination between the direct effect of MV infection
on the lymphocyte population and the host responses to
infection and lymphopenia (Figure 1o).
Vaccination of NHPs with vaccine strain-based rMV
expressing a fluorescent reporter protein did not result
in systemic replication and viremia, and instead resulted in
high levels of protection from wild-type MV infection [61].
Consistent with this finding, no overall change in antibody
repertoire was observed in measles-mumps-rubella vacci-
nated children [58]. Altogether, these observations signify
that measles vaccination does not lead to immune amne-
sia, but rather protects the host from it [62].
Conclusions
Experimental MV infections in primate models alongside
clinical studies in unvaccinated measles patients have
shed light on the complicated nature of MV as a
dual-tropic virus that can infect different types of cells
(Figure 1p). Moreover, it was elucidated how MV
lymphotropism drives measles-associated immune sup-
pression. Understanding the tropism and pathogenesis of
MV in turn underlines the fact that measles is not an
innocent childhood disease and that measles vaccination
not only protects against measles, but indirectly also
against other infectious diseases.
Conflict of interest statement
Nothing declared.
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