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Pathogenesis of measles virus infection

| December 23, 2012


Measles is a highly contagious disease caused by an enveloped RNA virus of the genus Morbillivirus in the family of Paramyxoviridae (Griffin et al, 1994). It is a major cause of child morbidity and mortality, particularly in developing countries, despite the introduction of attenuated measles virus vaccines which have greatly reduced the incidences since the 1960s (WHO, 2009). The window period of infection for infants lies between the disappearing maternal antibody protection and vaccine administration (Manchester and Rall, 2001). In 2008, 164,000 measles deaths were reported and majority was children under five years old (WHO, 2009).

Affected individuals combat measles by generating cell mediated immunity to clear the virus and humoral immunity to provide long-term protection (Manchester and Rall, 2001). However, measles virus (MV) induces immunosuppression during infection and for weeks after recovery, rendering infected individuals susceptible to secondary infections (Griffin et al, 1994). The evidence of immunosuppression caused was first recognized in 1908 when von Pirquet reported that children lost positive skin test for tuberculin antigen during MV infection (von Pirquet, 1908).

Research has been carried in vitro and in vivo in order to define the pathogenesis pathways of MV. Immune responses to MV have been described on transgenic mice and cynomolgus monkeys models (Sato et al, 2007) suggesting that multiple potential mechanisms are linked to the virus-induced immunosuppression (Schneider-Schaulies et al, 2002).


Measles is transmitted via airborne exposure from coughing and sneezing or close contact with nasal and throat secretions. MV remains active in the air for up to two hours. It enters the body through the respiratory system and spread systemically by infecting lymphoid cells. Infection and spread is a complex process. The structure and proteins of MV are important determinants of virus tropism and pathogenesis (Yanagi et al, 2006).

Measles virus consists of a non-segmented single negative-strand RNA genome (16,000 ribonucleotides) with a diameter of 150 to 300 nm. The outer envelope comprises with the inner matrix protein to form a lipid bilayer surrounding the viral genome. It encodes six structural proteins and two nonstructural proteins which are important for attachment of the virus to the host, replication and spreading of the virus in the body (Horikami et al, 1995).

Table 1 briefly describes the functions and locations of structural components and

Figure 1 illustrates the structure of a measles virus.

Table 1: Locations and functions of Measles virus structural proteins

Structural proteins




1. Haemagglutinin(H)



Both H and F proteins are surface transmembrane glycoproteins. They project from the lipid bilayer and traverse the internal matrix.


Responsible for the initiation of infection.

H protein: receptor binding and cell fusion

F protein: cell fusion and viral entry.


2. Fusion proteins (F)



3. Nucleoprotein (N) Surround the RNA strand Form a ribonucleocapsid.


4. Phosphoprotein (P)



Both P and L proteins are associated with the ribonucleocapsid The ribonucleoprotein complex acts as RNA polymerase and is responsible for RNA replication and transcription.


5. Large polymerase protein (L)


6. Matrix protein (M) Attaches to the inner surface of the envelope Assembly of the viral particles.

Virus budding.


Adapted from (Yanagi et al, 2006)

The nonstructural protein C and V are encoded on the P gene by RNA editing and alternative translation. Patterson et al (2000) showed that C and V proteins functioned as virulence factors in CNS measles infection using YAC-CD46 transgenic mice. In addition, C protein is capable to inhibit viral transcription and enhancing MV particles assembly. These proteins have shown to be involved in inhibition of interferon production (Naniche et al, 2000).

The infection process involves four steps:

1. Attachment

When measles virus enters the respiratory tract, the initial infection begins with viral attachment to host cellular receptors by the haemagglutinin (H) protein. The most studied receptors are CD46 and signaling lymphocytic activation molecule (SLAM/ CD150) (Ferreira et al, 2010). CD46 is a complement regulatory molecule and is present on all nucleated human cells whereas SLAM is only expressed on thymocytes, mature dendritic cells and T and B lymphocytes (Hsu et al, 2001). Other cell surface proteins such as moesin and substance P receptor were also proposed in MV binding (Kehren et al, 2001). The primary target for early stage infection has not been clearly defined. It was originally thought that respiratory epithelial cells were firstly infected (Griffin, 2001) but following the discovery of SLAM, some studies suggested that SLAM-positive immune cells should be the initial targets (Yanagi et al, 2002). Leonard et al. (2008) suggested the presence of a basolateral epithelial receptor (EpR) is necessary for entry of MV into respiratory epithelium and infection of the epithelial cells is required for shedding and transmission.

Figure 1: a) Structure of a measles virus

                        b) Measles virus genome

                        c) Membrane fusion and replication of measles virus in a cell

 Take from the wed-site

(Moss & Griffin, 2006)

2. Fusion

The interaction of both H and F proteins with human receptors is important for the virus to gain access into the host cell. Fusion (F) protein mediates the fusion of viral envelop with cell membrane. Figure 1 (c) demonstrated the fusion process. When the tetramer H protein binds to its receptor, it generates a conformational change within the F protein which is composed of two subunits F1 and F2 linked by a disulphide bond. The activated F protein inserts the hydrophobic fusion peptide into the target cell membrane and provides entry of the viral genome into the host cell interior (Weidmann et al, 1999).

3. RNA replication and Assembly of viral particles

The polymerase allows replication and transcription of the genome within the cell. The negative sense RNA is copied into a complementary positive strand which, in turn, acts as a template for the negative strand. Viral components are translated in the cell and are assembled at the cell surface (Yanagi et al, 2006).

4. Release of virus

MV leaves the host cell in a budding form (Yanagi et al, 2006).


The viremic spread from the respiratory tract is carried out by infected immune cells including monocytes, dendritic cells, B and T cells which travel through the local lymphatics and are transported to the secondary lymphoid tissue where further viral replication occurs. A secondary viremia occurs when infected cells enter the circulation and viral replication continues in the endothelia and epithelia of other organs including skin, gastrointestinal tract, liver, kidney and central nervous system (Ferreira et al, 2010). A systemic spread is favored by the immunosuppression following infection. Multiple mechanisms are involved in the development of immunosuppression and a brief description below focuses on some of the important pathways.

1. Changes in lymphocyte number and function

Lymphopenia of B and T cells during viremic and post-clinical recovery stages is demonstrated by many studies.

Bieback et al. (2002) showed that MV can bind to Toll-like receptor (TLR) 2 on monocytes, inducing SLAM expression and interleukin-6 (IL-6) production. In addition, binding of SLAM can induce Fas (CD95)-mediated apoptosis of uninfected CD4+ and CD8+ T lymphocytes.

The extracellular composition of CD46 is characterized by four short consensus repeat (SCR) and a STP domain. SCRs 2, 3 and 4 are binding regions for C3b and C4b, thereby preventing them from causing autologous complement lysis. The attachment of MV to SCRs 1 and 2 alters the normal signaling pathway resulting in down-regulation of CD46, eventually leading to increased C3b-mediated complement lysis (Manchester and Rall, 2001).

MV also inhibits lymphoproliferation by causing cell cycle arrest in the G0/G1 phase in dividing lymphocytes (Niewiesk et al, 1999) and interferes with NF-kB signaling pathways and anti-apoptotic B cell lymphoma 3 (Bcl-3) proteins (Bolt & Berg, 2002). Furthermore, Nucleoprotein of MV binds to the Fc-gamma receptor on antigen presenting cells and impairs their ability to stimulate T cell proliferation (Hehren et al, 2001). Figure 2 summarized the main pathways leading to immunosuppression.

Figure 2: Mechanisms of immunosuppression following measles virus infection

Mechanisms of immunosuppression following measles virus infection

Adapted from

(Moss et al, 2004)

2. Shift in cytokine profile

Early evasion of the innate immune responses is the interference of interferon-alpha/beta signaling pathways (Naniche et al, 2000) due to inhibition of STAT1 and STAT2 phosphorylation by proteins V and C. However, IFN-gamma production is not affected in the acute phase of measles (Takeuchi et al, 2003).

Cross-linking of CD46 by MV and direct binding of MV to CD46 on monocytes and dendritic cells inhibit the production of IL-12 (Karp et al, 1996) and hence suppress macrophage activation, T cell proliferation and delayed-type hypersensitivity (Atabani et al, 2001). The loss of IL-12 also decreases type 1 cytokines TNF-alpha and IL-2, leading to transition to type 2 cytokines IL-4, IL-5 and IL-10 by CD4+ T cells (Moss et al, 2002).

Th1 to Th2 shift leads to a change of cell-mediated immunity to a dominant humoral immunity which is not sufficient to combat new infections (Kemper et al, 2003).

3. Impaired antigen presentation

Dendritic cells are critical for the antigen presentation to naïve T lymphocyte. MV infected dendritic cells fail to undergo differentiation to become mature effector cells and some of them are susceptible to Fas-mediated apoptosis (Servet-Delprat et al, 2000). Marttila et al (2001) reported that antigen processing of other viruses such as rubella virus and coxsackie B4 virus is compromised in MV-infected human mononuclear cells, suggesting impaired antigen presentation to T cells.


The clinical presentation is induced by the immune responses. The initial encounter of the virus activates the innate immunity with high levels of IFN-γ and IL-8 but it is not efficient to clear the virus, leading to rapid multiplication of virus (Sato et al, 2008). Figure 3 illustrates the timeline of viremia and appearance of symptoms.

Figure 3: Pathogenesis of measles virus and immune responses of host.


Obtained from

(Hunt, 2008)

The early symptoms of measles, listed below, usually appear after an incubation period of 10 to 12 days and last for 2 to 4 days due to inflammatory reactions affecting the respiratory tract and conjunctiva (Griffin, 1995).

  • Fever
  • Malaise
  • Coryza
  • Cough
  • Small white spots in the oral cavity (Koplik’s spots)
  • Conjunctivitis
  • Rash

The appearance of maculopapular rash reflects the immune complex formation in the skin. It correlates with viremia and onset of adaptive immune responses. The rash starts on the face and upper back after 14 days of exposure and spreads to the entire body over the next 3 days and finally fades after 5 to 6 days indicating that Cytotoxic T lymphocytes destroy infected host cells and clear the virus. Measles antibodies also appear in the circulation around this time with IgM at day 10 and IgG at day 14. They reduce measles viral load through serum neutralization. IFN-γ and IL-8 levels decrease at convalescent as cytotoxic T cells decline (Heffernan and Keeling, 2008).


The most important pathologic feature of measles virus is immunosuppression. Most measles-related deaths are caused by secondary bacterial and viral infections. Malnourished children with weakened immune system and vitamin A deficiency are at high risk of developing complications which include blindness, diarrhoea, bronchitis, encephalitis, ear infection and pneumonia. Patients with impaired cell-mediated immunity may not develop the rash and they are susceptible to giant cell pneumonia (Manchester and Rall, 2001)


There is no antiviral therapy for measles although medications can reduce complications. Vaccination is currently the best method to prevent the disease. The first MV called Edmonston strain was isolated in 1954 on primary human kidney cells and it was subsequently adapted to chicken embryo fibroblasts and become the progenitor for currently used attenuated live vaccines. Composition of vaccines is important to elicit long-term protective immunity but not immunologic reactions and clinically significant immunosuppression. Measles vaccine is now usually given as part of a trivalent combined vaccine, MMR which is also against mumps and rubella (Hilleman, 1999). The World Health Organization has recommended infants should have the first administration of measles vaccine at 9 to 12 months because immunity requires Th1-type response. For countries with high measles transmission, a second dose should be given at age 15 to 18 months (WHO, 2009).

Vaccination campaigns are effective in promoting the use of vaccination and reducing measles deaths. Between 2002 and 2008, measles vaccination has significantly reduced 78% of measles deaths from an estimated 733 000 in 2000 to 164 000 in 2008. However, many developing countries, particularly parts of Africa and Asia, still suffer from this preventable infection due to the poor access to vaccinations and lack of facilities to properly store vaccines (Manchester and Rall, 2001). Ohtake et al (2010) has reported a spray drying method was successful to produce heat-stable measles vaccine powders. However, further tests are required to demonstrate the feasibility of these dry vaccines. Molecular epidemiology is a useful tool to monitor measles and genomic study of measles virus can provide insight in the development of new and safe vaccines (Ohtake et al, 2010). The World Health Organization is making an effort to monitor outbreaks and increase immunization coverage and hopefully can eventually eradicate the virus in the future.

Subacute sclerosing panencephalitis (SSPE)

SSPE is a fatal disease caused by a persistent infection with a defected form of measles virus in the brain. The common mutated components are the matrix (M), the fusion (F) and the haemagglutinin (H) proteins. Mutations can be point mutations, deletions and biased hypermutations and are mostly found in the M gene (Gutierrez et al, 2010).

SSPE has a slow progression and usually develops in an interval of 5 to 10 years after the initial infection. It is very rare. Incidence rate varies between countries but the average is about one per million. Age and sex of infected individuals can affect the frequency of SSPE. Infection before the age of 2 years is associated with higher occurrences and boys are 2 times more likely to acquire SSPE (Gutierrez et al, 2010).

The development of SSPE is caused by an imcompleted eradication of MV due to inadequate cell-mediated responses caused by genetic polymorphisms (Yentur et al, 2005) and high level of IL-4 but low levels of IL-12. These cytokines favour humoral response and predispose to viral replication (Hara et al, 2006).

MV enters neurons by binding to host receptors CD46 and CD9 using the F protein. It replicates inside the cells and spreads to neighbouring neurons by neurokinins synaptic receptors (Makhortova et al, 2007). In addition, sequence analysis of viral RNA showed that the virus was entered from one point and disseminate throughout the brain. The defective structural envelope proteins assist them to escape from the immune system as the mutated M, F and H proteins failed to assemble and bud out the cells. Thus, the viral particles are not recognized for many years. However, inflammatory responses are finally triggered when the virus damages the host DNA and induces apoptosis (Oldstone et al, 2004).

Histological examination of the brain tissue shows evidence of widespread demyelination, infiltration of immune cells and blood brain barrier damage. Glia cells and astrocytes may be activated with increased expression of MHC class II molecules and tumor necrosis factor-α. Appearance of inclusion bodies in brain tissue is also common (Akram et al, 2008).

Patients are often diagnosed based on presentation and clinical findings of electroencephalography, magnetic resonance imaging and CSF serology (Koppel et al, 1996). SSPE has four clinical stages (Table 2) and most patients died within 3 years of diagnosis (Gutierrez et al, 2010).

Table 2: Clinical stages of SSPE


Clinical manifestations


Personality changes

Behaviour abnormalities



Motor decline



Progressive unresponsiveness



Akinetic mutism (Loss of ability to speak and move)

Adpated from Gutierrez et al, 2010


Word count: 2421 excluding references and plagiarism statement.


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