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Measles virus (MV) is an acute infectious disease associated with childhood. It is classified in the genus Morbillivirus and belongs to the family Paramyxoviridae which include a wide range of animal diseases including canine distemper virus (CDV) and rinderpest virus (RPV), a disease seen in cattle1. In the developed world a measles infection is not seen as life-threatening with a mortality rate of 1:1000 cases1. This is primarily due to the large uptake of measles vaccination. In the developing world measles is noted as the cause of death in up to 5% of children under 5. This increase in mortality has been associated with under nutrition and susceptibility to secondary infections2. Its symptoms manifest as a cough, fever and the appearance of a maculopapular rash. The mode of transmission for MV is via aerosol droplets so the infection is initiated in the respiratory tract but can spread to a large number of organs and the central nervous system (CNS) 3. Its presence in the CNS can lead to the development of the disease subacute sclerosing panencephalitis (SSPE). The fact that this disease can develop several years after the initial measles infection shows the pathogenesis of MV to be a complex one.
Infection and spread
The measles virus is enveloped and made up of a non-segmented negative-strand RNA genome. This genome consists of 6 genes that code for 8 proteins, two of which are non-structural (V,C) The function of the other proteins can be grouped as those used in replication of the viral RNA (N, L, P) and those that form the viral envelope along with lipids from the host membrane (H,F,M)4. The hemagglutinin (H) and fusion (F) proteins are both glycoproteins present on the surface of the virion. Both are responsible for initiating infection of an exposed cell. MV enters these cells by fusing with the cell surface membrane. This process occurs at a neutral pH3. The H protein binds to receptors on the cell surface which in turn exposes the F protein which inserts into the membrane of the cell. The matrix protein (M) provides a link between both the H and F proteins and the nucleocapsid containing the genome and is involved in the budding process of the virus from the membrane after replication5.
The two main cellular receptors for MV are CD 46 and CD150 (signalling lymphocytic activation molecule, SLAM). CD 46 is found on the surface of all nucleated cells and plays a role in protecting cells from complement mediated cell lysis by binding complement components C3b and C4b6. Binding to this receptor will not only increase the cells susceptibility to cell lysis through its downregulation, but also can have implications on the host's immune response to the infection such as cytokine production7. CD46 receptors are seen mainly in tissue cultured strains of the virus as well as those attenuated strains used for vaccines.
CD150 is expressed on certain cells of the immune system including immature thymocytes, activated lymphocytes and antigen presenting cells (APC) 8, 9. The presence of CD150 on the cell is the main factor in the lymphotropism of MV infection in vivo10 and is seen as the main entry receptor for wild type MV11.
As the MV is transmitted via aerosol droplets this indicates that the endothelial cells of the respiratory tract would be the primary site of infection. These cells however do not express CD150 so it is unclear as to how the disease progresses. Some in vitro studies have suggested that there is an alternative receptor (receptor X) that has a role to play in the initial respiratory epithelial cell infection12, 13, 14. Measles virus has been shown to be present at both at the apical surface of infected epithelial cells in vitro and at the basolateral surface15. A recent study has suggested that the role of epithelial cells in the transmission of infection is minimal with the in vivo arm of the study claiming that any epithelial infection was instigated on the basolateral surface through close contact with MV infected APC's16.
Other molecules that may have a role in MV transmission from the respiratory tract include dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). It is not seen as an entry receptor but its inhibition does prevent infection of DCs and so it has a role to play in enhancing the function of the CD46 and CD150 receptors17.
Infection progresses from initial infection at respiratory mucosal surfaces to the lymphatic tissue and MV has been shown to be present in organs of the body including the gut, lung and skin, in epithelial cells, endothelial cells and macrophages18. After replication of the viral RNA and synthesis of the required viral components, the MV leaves the cell through the cellular membrane by a process known as "budding" which results in the viral envelope containing material derived from the plasma membrane of the infected cell. This is illustrated in the diagram below.
Figure 1: Measles virus replication
Nat Rev Microbiol. 2006; 4(12):900-8.19
Within the lymphoid system the MV infects T cells, B cells and macrophages. Replication in these cells greatly increases the number of virions and allows infection to progress to other organs via the bloodstream or though infected cell interactions which can lead to the presence of giant multinucleated cells or syncytia in MV infected tissue20.
The respiratory epithelium acts not only as a physical barrier but has shown to aid the immune response through the production and release of pro-inflammatory cytokines such as IL-8, a chemoattractant21. The hosts response to the infection is essential to confer long term immunity against MV.The innate immune response against a viral infection means the activation of NK cells and the production of interferons (IFN) Î± and Î². CD8+ T cells are activated through the presentation of endogenously derived viral proteins via MHC class I molecules on the surface of the cells. The presence of virus specific CD8+ T cells correlates with the onset of the rash and is seen the beginning of viral clearance from tissue22. Viral antigen taken up by APCs e.g. DCs is presented to CD4+ cells in the nearest draining lymph nodes. CD4+ T cells initiate a Th1 response to the viral infection with the production of IFN-Î³ and IL-2 which leads to macrophage activation and inhibition of a Th2 type response.
The activation of the Th1 response is short lived and is soon replaced by a more prolonged Th2 response through the release of cytokines such as IL-4, IL-10 and IL-13. These supress the activity of the Th1 response and allow for a more specific action through the production of antibodies. The onset of rash is leads to the production of Ig M antibodies which are used in the laboratory diagnosis of measles23. The Th2 response leads to the production of IgG antibodies which are MV specific. IgG1 and IgG3 are the most common IgG subtypes seen with measles infection though higher levels of IgG4 can be seen in convalescence24.
The characteristic symptoms of a measles infection are evident 10-14 days after initial infection. Characteristic symptoms include fever, cough and conjunctivitis. White spots known as Koplick spots can appear on the buccal mucosa of the mouth but usually disappear after 1-2 days. The main symptom of a measles infection is the presence of a maculopapular rash initially on the face which then spreads to the extremities. The rash is indicative of the immune response to MV and has shown not to be present in some immunocompromised patients25.
For the most part measles is a self-limiting disease with exposure inferring long lasting immunity against subsequent infection. However for certain groups such as the very young, those suffering from malnutrition, vitamin A deficiency and the immunocompromised, measles can lead to severe complications and even death25, 26. This is due to immunosuppression with the result that a secondary infection in an MV infected individual may have a more serious outcome than normally expected. Such secondary infections can lead to diarrhoea and pneumonia which are among the most common causes of death from secondary infection19.
MV-induced immunosuppression has a number of characteristics. The first of these is lymphopenia. A significant reduction in CD4+ T cells, CD8+ T cells, B cells as well as neutrophils and monocytes is seen in acute measles cases with apoptosis of both infected and non-infected cells thought to be a cause27, 28. This immunosuppressive characteristic is shown to be more prevalent in a younger population and is quickly resolved with T cell numbers recovering in a few days29.
Immunosuppression is also caused by a shift in the production of cytokines from those involved in cell mediated immune response to those that promote the formation of antibodies. This is the natural progression for the clearance of MV from the body but this Th2 response is evident in the immune system for a number of weeks after viral clearance. As a result the immune response to any secondary infections will be supressed and the body maybe overwhelmed. The suppression of cytokines such as IL-2, IFN-Î³ and a switch to the production of cytokines such as IL-4 inhibits the Th1 response and increase susceptibility to intracellular pathogens30. It also leads to supressed delayed type hypersensitivity (DTH) as evident in supressed tuberculin reactivity for a number of weeks after measles rash has cleared31. The production of IL-12, a cytokine that promotes Th1 cell differentiation and NK cell activation, by DCs is also supressed after a measles infection32, 33. In vitro studies have linked this to the binding of MV to CD46 of DC's34. DCs express both of the main receptors for MV but as stated earlier CD46 does not interact with wild-type MV as efficiently as CD150 so the role of CD46 in suppression of IL-12 in vivo remains unclear. An increase in the amount of IL-10 produced also prolongs the Th2 response. This increase may be due to the interaction of MV with the previously discussed lectin DC-SIGN which is present on the surfaces of DCs. This interaction leads to the activation of a signalling pathway which culminates in increased production of IL-10 by the DC35.
Lymphocyte proliferation is also suppressed for a period after MV infection. This is seen in a lack of response to stimulation from mitogens, with a decrease in the production of IL-2 seen36. Cell cycle arrest at G1 phase has also been described in in vitro studies of infected lymphocytes37, 38. The interaction of MV and CD 150 may also have a role to play as CD150 is involved in T-cell proliferation and the production of IFN-Î³39. Its interaction with MV leads to reduced receptor expression on the surface of T cells and thus reduced T cell production40.
The measles virus is a live attenuated virus. There are several different types available including Swartz, Edmonston Zagreb and Moraten. The latter being the only measles vaccine licenced for use in the U.S. Most of the vaccines in use are derived from a strain of the wild-type virus (Edmonston) that had been altered by passage through a chicken embryo system a number of times to decrease virulence41. MV is an antigenically monotypic virus. This means the proteins that are involved in producing an immune response have not altered over time. Therefore the vaccines developed previously still provide protection against vaccine strains today19. The vaccine is available as a single-virus vaccine but is typically given with vaccines for mumps and rubella (MMR). Due to the contagious nature of the vaccine a high uptake in vaccination is required in order to prevent outbreaks of infection. The level of immunity in the community needs to be between 93-95% to prevent loss of herd immunity42. The elimination of the measles virus in the developing world is hindered by a number of factors including the necessity for a cold chain to be maintained during immunisation programs as well as sterile equipment and trained personnel43, 19.
The passive maternal antibodies acquired by the infant in the womb as well as an immature immune system, have shown to be obstacles in the effective immunisation of infants younger than 12 months of age44. As a result, in most developed countries two doses of the vaccine are administered; the first at approx. 12 months of age and the second between the ages of 4-645. Seroconversion is seen in > 99% after the second dose42. In countries where MV is endemic, a single dose at 9 months has been recommended because of the high risk associated with the contraction of measles at such an early age. A seroconversion rate of only 85% is seen as a result and this can lead to a higher susceptibility to the disease in this age group42.
The immune response to the measles vaccine is both cell-mediated and humoral with both the presence of IFN-Î³ and IL-4 detected46. Antibodies are present in the body 12-15 days after vaccination, with the greatest amount detected between 21-28 days19. However the levels of antibody produced and the duration of the antibody titres has shown to be inconsistent and shorter than those acquired through a wild-type measles infection47, 48.
Subacute sclerosing panencephalitis
Subacute sclerosis panencephalitis (SSPE) is a disease of the central nervous system (CNS) which can occur after infection with the measles virus. The incidence of the disease is rare with individuals vaccinated against MV less likely to contract SSPE49. For every 100,000 cases of measles reported, 4-11 cases are expected to occur49. In children the disease has a survival time of less than 3 years50. SSPE first presents between the ages of 8 and 11 years and can present 2 to 10 years after initial measles infection51, 52. Risk factors include the age at which the initial measles infection occurs, older age of the mother, poverty, overcrowding and living in a rural environment53. The disease is twice as common in males as in females54.
The normal immune response to measles infection involves an initial cell-mediated Th1 response to remove the infected cells. A humoral response then follows to provide long term immunity against MV. It is thought that the pathogenesis of SSPE involves an inadequate cell mediated immune response to MV with lower levels of INF, IL-2, IL-10 and IL-12 being produced55 . This leads to a premature humoral response resulting in a failure to effectively clear the infection. It is thought that there is a role for CD46 in the infections ability to enter neurons56. Once inside these cells the virus mutates its proteins to avoid recognition with mutation of the matrix gene common57. MV can remain dormant for years before becoming evident. It is the subsequent immune response that leads to CNS destruction.
The highly contagious nature of MV means the goal of measles eradication is still some distance away especially in areas where diseases that affect the immune system such as HIV/AIDS are rife. The continued drive to deliver MV vaccination to all children is paramount in the drive to eliminate measles and diseases associated with it.