Discuss the pathogenesis of measles virus infection

Introduction

Measles virus (MV) is a member of the paramyxovirus family and has a single stranded RNA genome. The viral genome encodes for six structural proteins: Haemagglutin (H), Fusion (F), Nucleoprotein (N), Phosphoprotein (P), Large (L) polymerase protein, and Matrix (M) protein and two non-structural proteins: C and V (Griffin, 2010). The structure of the virus is shown below.

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Fig 1. The structure of the Measles virus

Ref:http://www.microbiologybytes.com/virology/Paramyxoviruses.html

The majority of measles cases occur in children and in those who are fit and healthy, results in life long immunity without complications. Measles virus has been eliminated in the western world since 2000 through an efficient vaccine programme, however, it is a different scenario in developing countries were deaths arise due to lack of vaccine administration and malnourishment of children (Fontana et al, 2008).For example in 2008, 164 000 people died from measles virus of these 95% were in low-income countries (www.who.int/mediacentre/factsheets/fs286/en/). Although infection with MV produces an efficient immune response that is maintained for the rest of the individuals life, it also results in a transient state of immunosuppression that can last for several weeks. This leaves the patient susceptible to secondary infections by opportunistic pathogens which account for the majority of measles associated deaths (Sevet-Delprat et al, 2000).The exact mechanism of the immunosuppression is still unknown however many theories have been suggested.

Infection and Spread

The MV is spread through aerosol transmission in the cough or sneeze of an infected person. The virus is extremely contagious and can remain in the air or on a surface for up to two hours (Stalkup, 2002). The route of entry for the virus is through the respiratory tract and once infected, the virus will incubate for an average of 10-12 days before any symptoms are seen. Infection is initiated by the attachment of the H protein to the host cell receptors, which results in the fusion of the envelope of the virus with the host cell membrane. This fusion of membranes causes the release of viral RNA into the host cell cytoplasm. After the RNA has replicated, using host cell machinery, new virus particles are assembled using the M protein and bud from the host cell membrane to infect other susceptible cells (Swart, 2008). The host cell receptors for the measles virus are CD46, a complement regulatory protein that is found on all nucleated cells and the Signalling Lymphocytic Activation Molecule (SLAM/CD150) which is found on the surface of both T and B lymphocytes as well as macrophages and mature Dendritic cells (DC) (Yanagi et al, 2006). In vitro studies have found that vaccine strains of the measles virus use CD46 and SLAM as their receptor however wild-type MV only recognizes CD150 (Ferreira et al, 2010). There has been some debate over the exact cell that is involved in the initial infection with MV. It had previously been thought that the virus infected epithelial cells lining the nasopharynx (Stalkup et al, 2002) however more recent studies have shown that these cells do not bear the MV receptors SLAM which facilitate wild-type viral infection therefore further studies are required to identify this unknown receptor . It has been suggested that alveolar macrophages and DC lining the respiratory tract are the initial cells involved in measles infection.This was demonstrated in a study using mice that expressed humanized SLAM. These mice were infected intranasally with wild type measles virus expressing green fluorescent protein. The nasal associated lymphoid tissue (NALT) was then extracted from these mice at different time points (1,2 or 3 days). Results showed that alveolar macrophages were the first cells to be infected by the measles virus and not the epithelial cells (Ferreira et al, 2010).

DC’s are the main antigen presenting cells of the immune system and are used by other viruses to infect lymphocytes for (example the HIV virus) (Witte et al, 2008). Therefore DC may provide an important route of transport for MV to secondary lymphoid tissue. The role of DCs in measles infection is further indicated by the identification of DC-SIGN which is an accessory receptor that has been identified on MV susceptible cells and is thought to assist MV infection of CD150 expressing DCs (Yanagi, 2006). Furthermore, large numbers of DC-SIGN positive DCs have been found to be present in the epithelium of the respiratory tract which demonstrates their potential primary role in MV infection of (Ludlow et al, 2010 ; Witte et al, 2008).

An alternative theory is that epithelial cells are infected in the latter stages of infection by lymphoid cells facilitating viral spread by the respiratory route. This would mean that epithelial cells are infected at the basolateral cell surface rather than the apical surface. This was demonstrated by a study that looked at mutated MV strains that could not bind to the as yet unidentified Epithelial Cell receptor (EpR) but could still recognise the SLAM receptor. Results showed that the macaques developed the rash but could not shed the virus which suggests that the EpR is a basolaterally expressed protein that is important for the spread of the virus at the infective stage (Leonard, et al, 2008). A study by Ludlow (2010) supported these findings by showing that wild type MV could not infect primary columnar epithelial cells by the apical surface further demonstrating the potential role of epithelial cells in latter stages of infection rather than initial stages as previously thought.

In response to viral infection the innate immune system responds by producing inflammatory cytokines to protect cells from viral infection. These cytokines include type 1 interferons (IFN) such as IFN? and ? which are induced in response to RNA viruses. IFNs induce an anti-viral state in neighbouring cells and increase the expression of class 1 Major Histocompatibility Complex (MHC) molecules on the infected cell surface which will present the viral antigens to CD8+ T cells. CD8+ T cells clear the infection by cytotoxic T cell mediated killing of the infected cell (Abbas & Ltchtman, 2005). To overcome these host cell defences, viruses have ways to evade the immune system. MV virus protein V and C have been shown to downregulate IFN production in vitro and this includes both attenuated and wild type strains (Fontana et al, 2008). Through the inhibition of the proinflammatory cytokines MV can infect more host cells. MV may also use the innate immune system to enhance viral spread and pathogenesis by using Toll like receptors (TLRs) which are found on the surfaces of cells that activate the immune system by recognising bacterial and viral pathogens. The binding of TRL2 on human monocytes by MV H protein has been shown to induce production of interleukin 6 (IL-6) which upregulates expression of SLAM the primary receptor for MV (Beiback et al, 2002).

Once the virus is picked up by antigen presenting cells it is carried to the secondary lymphatic tissue were it can replicate in T cell, B cells and activated monocytes with lymphocytes being the main target cell of MV infection (de Swart et al, 2007). These infected cells can be seen in the blood 7-9 days after infection (Griffin, 2010). It is thought that through these infected lymphoid cells that the virus is able to infect epithelial and endothelial cells lining organs including the liver, brain and skin (Moench et al, 1988). In order for MV to infect these organs it must overcome these endothelial cell barriers.It has been shown in cell culture that wild type MV infection may infect endothelial cells by increasing the expression and activation of leukocyte integrins which bring infected T cells into close contact with these cells leading to their infection (Dittmar et al, 2008).

Symptoms

The initial symptoms of MV are very similar to those of the flu including runny nose, conjunctivitis and cough which is accompanied by a fever of 104-1050F that lasts up to 4 days (Stalkup, 2002). The characteristic feature of MV is the red rash that appears beginning on the face and behind the ears, which spreads to the rest of the body (please see Fig 2 below). During this time the person is highly contagious and remains so until the rash disappears (www.cdc.gov/vaccines/pubs/pinkbook/download/meas.pdf).

Fig 2 shows a child with an extensive rash caused by the Measles virus.

Ref: http://www.vaccineinformation.org/measles/photos.asp

Small white spots known as Koplik spots may also be seen in the inside the mouth which is a diagnostic indicator of measles and appear one day before the rash (Perry & Halsey, 2004). The appearance of the rash is due to the immune systems attack of the systemic infection of epithelial cells and biopsies of the rash have shown infiltration of CD8+ and CD4+ T lymphocytes in the rhesus monkey (Permur et al, 2003). An individual who in infected with measles virus will recover within about 10-14 days but may remain vulnerable to secondary infections including pneumonia and diarrhoea for a few weeks.This was first noted by von Pirquet who noticed that individuals recently infected with the MV failed to respond to the tuberculin skin test and this has led to many studies into the reasons for this immune suppression (Griffin et al, 1994).

One reason for the immunosuppression seen after a measles infection is the switch from a T helper 1 (Th1) CD4 response to a T helper 2 (Th2) CD4 response. Initial MV infection results in the production of a Th1 response which is necessary to eliminate the pathogen and is marked by increased production of IFN? however as the rash is cleared this changes to a Th2 response which is important in the production of measles specific antibodies (Moss et al, 2004). Th2 cytokines IL-4 and IL-10 have been shown to be elevated for weeks in those who have had MV (Moss et al, 2002). IL-10 suppresses the immune system by inhibiting lymphocyte proliferation and macrophage activation therefore may have a key role in failure to generate a Th1 response after MV infection (Sato et al, 2008).

IL-12 is primarily produced by activated macrophages and DCs and has a pivotal role in the generation of a cell mediated immune response as well as directing CD4+ T cells to differentiate into Th1 cells (Abbas & Lichtman, 2005). Studies have shown that MV infection of DCs inhibits IL-12 production which would lead to an environment favouring a Th2 cell response (Servert-Delprat et al, 2000). Furthermore peripheral blood monocytic cells taken from patients with measles have been shown to have a prolonged decrease in IL-12 (Atabani et al, 2001). Stimulation of DCs through TLR4 also results in inhibition of IL-12 in mice expressing human SLAM receptor (Hahm et al, 2007).

As lymphocytes are the main targets for MV infection and replication the immunosuppression seen after infection may be due to as decrease in circulating lymphocytes. However, studies have shown that lymphocyte numbers quickly return to normal levels and therefore cannot account for the immune suppression seen weeks after infection (Griffin, 2010).

Subacute Sclerosing Panencephalitis (SSPE)

SSPE is a rare neurological complication of MV infection that affects 1 in a million measles cases although there is an increased risk with children infected with the measles virus before age 2 and males more than females (Norrby & Kristensson, 1997). The characteristic symptoms of SSPE are deterioration of mental and motor functions as a result of destruction of brain tissue. These symptoms typically begin to manifest 7-10 years after primary viral infection and ultimately result in death within 2 years (Stalkup, 2002). Patients with SSPE have high levels of measles specific antibody circulating in their blood and cerebrospinal fluid (CSF) yet the virus is not eliminated (Barrero et al, 2003). It is thought that the virus mutates inside the neurons which allows it to evade the immune system however these mutations may alter the host cells leading to the generation of the immune response (Gutierrez et al, 2010). However the mechanism by which neurons are infected is still unknown as no receptors have been identified. There is no cure for SSPE although treatment of individuals with Interferon ? and Isoprinosine has been shown to slow down the progression of symptoms in some individuals (Gascon et al, 1993).

Vaccination

The first MV vaccine was produced in the 1960s which was formalin-inactivated with alum. This vaccine produced a condition known as atypical measles which resulted in some individuals experiencing symptoms which were often worse than wild-type measles, when they came into contact with someone who had measles (deSwart, 2008). In 1963, Enders measles vaccine was developed which was a live attenuated vaccine (Stalkup, 2002). This vaccine is grown in cell culture fibroblasts from chicken embryos and is unable to produce its full pathogenic effect but induces an adequate life long immune response (P?tz et al, 2003). The measles vaccine has resulted in a 99% fall in the number of measles cases that were previously seen annually in the United States (Stalkup, 2002). MV could potentially be irradicated but this is dependent on high vaccine coverage. The World Health Organization (WHO) has a policy in place which has set a goal of reducing the death rate from MV in children under 5 by 2015 (http://www.who.int/mediacentre/factsheets/fs286). MV infection can also lead to blindness in children who are Vitamin A deficient and the WHO have recommended that all children with measles are given vitamin A supplementation to combat blindness (Semba and Bloem, 2004).

The measles vaccine is part of the Measles Mumps and Rubella (MMR) vaccine that is given in two doses. The vaccine is administered intramuscularly and the first injection is given to children around 13 months (http://www.nhs.uk/conditions/mmr/Pages/Introduction.aspx). The vaccine is not given before this age because these children will have maternal antibodies which would interfere with the vaccine and not generate an appropriately high enough immune response (Moss et al, 2004). A second dose of the MMR vaccine is given to preschool children as a booster as 2-5% of individuals fail to produce an appropriate protective immunity to the first inoculation

(http://www.cdc.gov/vaccines/vpd-vac/combo-vaccines/mmr/faqs-mmr-hcp.htm). New methods of delivery of MMR vaccine have been investigated such as the use of aerosol vaccine which would mimic natural measles infection and the use of DNA vaccine administration. Aerosol vaccine has been found to generate an effective immune response that is equal to that of the currently used vaccine and may also overcome the interference from maternal antibodies however clinical trials are still in progress (Heno-Restrepo et al, 2009). Furthermore, trials into the use of DNA vaccines have proposed a potential to vaccinate children as young as four months (Pasetti et al, 2009).

The MMR vaccine has been in the public eye for many years as a result of a paper by Wakefield and colleagues in 1998 which claimed that there was a link between the administration of the MMR vaccine and the development of autism (Farrington et al, 2001). Many studies have been carried out to either prove or disprove this study as these claims led to fear amongst parents regarding vaccination of their children and uptake fell to 80% between 2003 and 2004 as a result of this (Bedford & Ellimen, 2010). As stated in the introduction MV is so contagious even a minor drop in vaccine coverage can lead to a large number of cases. In 2010 after an extensive investigation by the General Medical council it was finally confirmed that the paper by Wakefield was unfounded (Godlee et al, 2001).

Conclusion

Although cases of MV are rarely seen in this country it results in the death of many children in the developing countries. Currently vaccination is given at 13 months of age however many studies are ongoing that could potentially provide a vaccine that could be administered earlier resulting in children being protected earlier and limiting hosts for the virus. Furthermore, malnutrition is one of the major contributing factors in the deaths from measles virus, tackling this problem would also decrease the mortality rate. As stated above MV poses a problem in that infection generates a life long immune response but also leaves the host susceptible to secondary infections. The exact mechanism for this is not yet known therefore more work is needed to answer this problem and potentially combat this immune suppression.

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