Measles is a contagious human disease that mainly affects children. The measles virus (MV) that causes this systemic infection is a single stranded ribonucleic acid virus belonging to the genus Morbillivirus in the Paramyxovirus family.(2,3) As transmission is via air droplets, initiation of the infection occurs in the respiratory tract, and spreads to other organs. MV affects the immune system leading to a prolonged state of immune suppression which can result in several complications involving the respiratory tract and the brain e.g. encephalitis.
Immunisation using a live attenuated vaccine is the main preventative of the infection. In 2000, the cases of infection of measles in Europe was rare due to vaccination, however in 2008 there was a total of 7,822 (5) with Switzerland having the highest incidence rate in Europe. (6) Measles are increasing in Ireland, with 320 cases reported within 8 months in 2009. (7) The objective of this assignment it to review the pathogenicity of measles, the symptoms associated with the infection and how to prevent this infectious and potentially fatal disease.
Infection and Spread
Infection is initiated in the respiratory tract. (8) The virus can then spread to the local secondary lymphoid tissues via dendritic cells of the lungs or the alveolar macrophages. (8) From here it can travel to the peripheral blood and spread via epithelial and endothelial cells to multiple organs. Research has suggested that in the later stages of the infection, the virus infects the epithelial cells of the respiratory tract facilitating in the spread of the virus. (9) But how does the virus invade its host?
MV is a non – segmented negative sense strand enveloped RNA virus that encodes 8 proteins: 6 structural proteins and 2 non-structural proteins. (8)
The first 3 structural proteins are combined within the RNA. The (N) nucleoprotein protects the genomic RNA by forming the ribonucleocapsid. The phosphoprotein (P) and large polymerase protein (L) are involved in viral replication. (4, 8)
The non- structural proteins C and V are responsible for the regulation of viral infection by interacting with cellular proteins. (11)
The F and H glycoproteins found on the surface of the virus envelope, are responsible for the initiation of infection to susceptible host cells. These transmembrane proteins allow the virus to fuse with the host cell, penetration of the virus into the host cell and haemolysis. (4) The F protein facilitates the spread of the virus from one cell to the other by inducing cell fusion. (4) Transcription occurs within the cell to create more negative sense RNA for assembly of new budding viruses (see figure 1). (10)
The matrix M protein is a non-glycosylated protein found in the inner lipid bilayer of the envelope. Its function is to connect the ribonucleoprotein complex to the envelope glycoproteins during viral assembly. (8)
The H protein of the virus surface is responsible for receptor binding. CD46 was the first identified receptor for MV and is present on all nucleated cells. (8) It was later discovered that the signalling lymphocyte activation molecule (SLAM) also known as CD150 has also been identified as receptor for MV. (3, 8) In fact the receptor binding of CD46 seems to be limited to attenuated vaccine strains rather than the wild type which seems to have better affinity for the CD 150 receptor. CD150 is expressed on many immune cells including lymphocytes, dendritic cells and macrophages and is a member of the CD2 subset of the Ig superfamily. (3, 8)
The structure of H protein of MV is well documented consisting of a globular head group composed of 6 anti-parallel B sheets. These are stabilised by two intra- monomeric disulphide bonds and partially covered with N-linked carbohydrates. (12) The binding regions for CD 46 and CD 150 (SLAM) are found adjacent to one another. (3)
It has been widely documented that CD150 is the initial receptor targeted by the H protein of the virus but little is known on the receptors involved in the infection of epithelial cells as these cells do not express CD150. (3) Tahara et al have resulted that “MV has the ability to infect both polarised epithelial and immune cells using distinctive receptor – binding sites on the H protein”. (3) His study used a CD150 negative human lung adenocarcinoma cell line (NCI-H358) to infect with the MV. The presence of the H protein was evident using monoclonal antibodies and suggesting that the H protein must have been using a different receptor binding site to infect the cells. (3)
The pathogenesis of MV, initiates an immune response. It triggers a cell-mediated immune response which involves the activation of TH1 and release of interferon ? and interleukin 2 (IL-2). (13) In the later part of the infection an antibody- mediated response provides long term protection against future infections. TH2 lymphocytes are produced as well as IL-4 which favours the induction of a humoral response which is important for long life protection against re-infection. (8, 13) However MV has the ability to dominate the immune system and use it to its advantage. The suppression of the immune system results in secondary bacterial and viral infection which attributes to the number of fatalities associated with Measles infection. Moss et al suggested that there are many mechanisms that develop to immune suppression following a MV infection. (14)
Immunomodulatory Cytokines (Increased IL-10 and IL-4)
IL-12 down regulation
Impaired Antigen Presentation of Dendritic cells
One of the clinical manifestations of MV is lymphopenia. This may be due to the reduction of CD4+ and CD8+ T lymphocytes. Increased surface expression of Fas (CD95) during acute measles suggests that unaffected T lymphocytes undergo apoptosis. (14) Abnormalities in the lymphocyte function are found during and after MV infection. The virus inhibits IL-2 dependent T lymphocyte survival and proliferation. This is in response to an impaired protein kinase B activation caused by the H and F proteins of the virus. (14)
In the acute phase of infection a T helper Type 1 (TH1) response is induced which shifts to T helper type 2 (TH2) in the later stage of infection which accounts for viral clearance and development of antibodies respectively. (8) The increased production of cytokines IL-10 and IL-4 in the TH2 response may be another mechanism for viral induced immunosuppression. IL-10 is an immunosuppressive cytokine which down-regulates the synthesis of cytokines and suppresses T cell proliferation and macrophage activation. (15) This prevents macrophage activation and TH 1 response to new infections. (8) As previously mentioned CD 46 is found on many immune cells including monocytes. As a result IL-12 produced by monocytes is downregulated. (16) IL-12 is essential for TH1 immune response. (15) The reduction in production of IL-12 favours TH2 and suppresses TH1 immunity. (17)
Dendritic cells play a critical role in the presentation of antigen to naive T lymphocytes. MV infection promotes maturation of dendritic cells but also alters its function (18) and mediates Fas induced apoptosis.
It is now established that the non-structural protein C and V produced by the P gene plays a role in immunosuppression by interfering with interferon ?/? signalling pathways. (8) These proteins of the MV inhibits phosphorylation of STAT 1 and STAT 2 which are transcription factors involved in the Interferon pathway. (14)
Clinical symptoms associated with measles include a fever and rash but a cough, coryza or conjunctivitis can also be seen. (9) It is after 10-14 days of infection that this characteristic rash is present and seems to be due to the individuals’ immune response to the virus. (8) The rash usually begins on the face and travels down to the extremities and can last for about 5 days before disappearing (4) Two thirds of patients show a white-marked enanthema on the buccal mucosa known as Koplik’s spot. (2) Koplik spots were first identified by Koplik in 1896 and are the pathognomonic of measles. (4, 5) Generally the resolution of the rash and fever begins after 7 to 10 days however the cough may persist for longer. (4) In many cases complication can occur resulting in infections of the respiratory tract and brain.
Pneumonia accompanying measles may be due to the MV or a secondary bacterial infection. (4) 60% of infants infected with measles, can die from pneumonia while older children (10 -14 years) death is associated with acute encephalitis. (4) It seems that viral infection of the CNS is a common feature of measles but only a proportion of patients will present with clinical symptoms.
Mild forms of measles have been observed due to passive immunity to the virus. Infants who have passively acquired antibodies to MV from the mother will present with some of the symptoms but depends on the degree of passive immunity that is achieved. (4) A study in China determined that mothers produced low levels of antibodies due to vaccination rather than natural infection. The outcome is reduced protection to the infant which can result in measles infection before the age of receiving a vaccine. (19)
Atypical measles is associated with patients who received a vaccine using a killed MV rather than live attenuated vaccine and subsequently was exposed to the wild-type measles virus. Patients present with a low or undetectable titre which drastically rises after a few days. (4) As the symptoms may vary to classic measles, it can be misdiagnosed. Atypical measles is more severe than classic measles. Research has shown that this may be due to the fact that the killed vaccine lacks the antigen to stimulate immune response by preventing the virus entering the cells. (4) It has been shown that the killed vaccine does not produces antibodies to the F proteins which facilitate cell entry and spread of the virus.
Immunocompromised patients present with severe measles due to their deficient cellular immunity. Secondary infections are often seen including pneumonia and encephalitis resembling SSPE. Malnourished children especially in the developing world can suffer from severe measles. This may be due to intense exposure due to crowding or the inability to produce a cell-mediated response due to malnutrition. (4)
Measles is regarded as an infection of childhood however adults do get infected and usually develop a severe form which can have complications. During pregnancy, an infected mother is not known to cause co-genital abnormalities to the foetus but may cause abortion or preterm delivery. (4)
The use of vaccines is the main preventative of Measles. The development of the first measles vaccine was in the 1960s. (20) Immunisation began with a inactivated (killed) vaccine, but resulted in short term protection and undeveloped immune system. (20) Immunisation with a live-attenuated vaccine can be administered as a monovaccine or in combination with mumps and rubella (MMR) or mumps, rubella and varicella virus (MMRV). (2) It is derived from a wild type of the virus known as Edmonston and processed through chicken cells. (8) In 1985, the measles virus was first introduced in Ireland, with the combination vaccine (MMR) emerging in 1988. (7) When the vaccine was first introduced in Ireland 9,903 cases of measles were reported. This dropped to 201 cases in 1987. (7) A two dose vaccine is essential for long lasting protection to the virus. (21)
There are occasions when passive immunisation is required using immunoglobulin which include immunocompromised patients such as HIV positive patients. (4)
Successful vaccination against infectious diseases depends on the vaccines ability to induce a protective response. Successful vaccination is dependent on the individuals’ human leukocyte antigen (HLA) haplotype which regulates the immune response. (22) There are two types of HLA proteins. The first, Class I consists of A,B and C alleles. These bind to CD8+ T lymphocytes. (23) Class II DR,DQ and DP alleles attach and present peptides to CD4+ T lymphocytes. (23)
The measles vaccine results in an iatrogenic attenuated measles infection. As mentioned previously, the C46 molecule serves as the receptor for the H protein of MV where it is broken down and presented to the immune system by the HLA system. (22) Studies have shown certain HLA alleles may impact differently on the responsiveness to the measles virus. (22)
For successful herd immunity to measles, most of the population needs to be immunised. However fears of the association of the MMR vaccine and autism have stopped parents from vaccinating their children. There is no scientific evidence to suggest any link with autism. (24)
Research has suggested that Vitamin A supplementation may help prevent Measles infection in infants prior to vaccination. (25)
Subacute Sclerosing Panencephalitis. (SSPE)
One of the persistent secondary infections of MV is subacute sclerosis panencephalitis (SSPE) which causes demyelination of the central nervous system (CNS). (13)
SSPE cannot occur without the presence of a direct measles and is found to be more prevalent in males than in females. (26) Research has shown that the earlier a patient is infected with MV the greater the risk of complications such as SSPE can occur. This is due to an immature immune system. (13)
The MV invades the neurons using the CD46 receptor and using its F protein. (13) There have been studies to suggest that another receptor CD9 aids entry into the cell. Once inside the cell the virus changes the machinery of the cells to avoid an immune response. It undergoes mutations of its own proteins to go unrecognised and reproduces within the neurons. (13) The virus can live as a “parasite” within the neurons for years. Finally it will damage the cell to an extent that apoptosis will occur and the immune system is triggered.
Onset of SSPE is usually 6 years after infection and clinical symptoms present as intellectual deterioration and behaviour abnormalities. Final stages include seizures, focal paralysis and death with akinetic mutism. (13)
There is no cure for this fatal disease only a preventative. Other fears related to the vaccine were that it may cause SSPE however there is no evidence to back this case.