Understanding the Measles Virus (MV)
Measles is a highly contagious disease caused by the Measles Virus (MV) which belongs to the Paramyxovirus family, and is of the genus Morbillivirus as it does not possess any virus-associated neuraminidase activity (Topley & Wilsons 2005, Morgan & Rapp 1977). It is primarily considered a childhood disease, easily communicable within a non-immunised population. Moreover, acute infection with the virus will confer lifelong immunity in most individuals (Schneider-Schaulies & Meulen 2000). Therefore as the virus is also confined to humans with no asymptomatic carrier state, to remain endemic within a population it relies upon infection of those still susceptible to infection.
The MV itself is approximately 100–300 nm in diameter, with a core of single-stranded RNA which encodes for 8 proteins, surrounded in a helical capsid (Griffin 2010; Schneider-Schaulies & Meulen 2000). Two viral transmembrane proteins; fusion (F) protein is responsible for fusion of virus and host cell membranes, viral penetration, and hemolysis. Hemagglutinin (H) is responsible for adsorption of virus to cells. Antibodies to these proteins may mitigate against infection of host cells (Griffin 2010). Other proteins include the matrix or M protein which links the envelope to the ribonucleoplasmid core, and the nucleoprotein (N) forms part of the ribonucleocapsid along with phosphoprotein (P) and large polymerase protein (L) which both are also necessary for RNA synthesis. Non structural proteins C and V also regulate response to infection (Topley & Wilson 2005). A schematic of the virus is shown in figure 1.
Fig 1. Adapted from Morgan & Rapp 1977 Schematic of Measles virus
Canine distemper and rinderpest viruses also belong to the same genus and share close antigenic relationship. In October 2010 the UN Food and Agriculture Organisation announced that Rinderpest had been successfully eradicated. Infection with measles also provided the first insight into suppression of the immune system by a virus, thus permitting secondary infections to occur relating to the mortality of infection (McChesney et al 1989). This area is of much interest to immunologists and was first noted over 200 years ago as TB infection was seen to follow measles infection (Karp 1999), of which alterations in cell mediated immunity is of most clinical concern. This was noted by von Pirquet whist performing the tuberculin skin test which failed to respond to it thus predisposing to secondary infectious from measles induced immunosuppression (Topley & Wilson 2005).
Isolation of the virus in 1954 by Enders and Peebles allowed the advent of measles vaccination, with the first vaccines being produced in 1963. Safe and effective vaccination programmes with the live further attenuated vaccine have eliminated the virus from most westernised societies (WHO weekly 2008); however the virus remains a major cause of mortality in populations lacking access to adequate medical care (Kerdiles et al 2006).
In 2008, 164 000 measles deaths were recorded globally (WHO fact sheet 2009) and as recent as January 2011 Kofi Annan called for the UN Executive Board to set an eradication date for measles (Measles Initiative 2011). Progress on this front continues with immunisation programmes and effective surveillance this is highlighted by the reduction of measles deaths by 78% between 2000 and 2008.
The measles virus normally enters the body through the upper respiratory tract, or conjunctiva. The first clinical sign of infection is usually a febrile illness (>38.3°c), which begins about 10 to 12 days after exposure to the virus, and lasts four to seven days (fig2). Further signs and symptoms then develop in this prodromal illness these include malaise, cough, coryza (runny nose), conjunctivitis, as the MV establishes a systemic infection involving multiple organ systems leading to Koplik spots and typical maculopapular rash and immunosuppression.
Fig. 2. Adapted from Topley & Wilson Microbiology & Microbial Infections Immunology 10th edt. 2005.
Transmission occurs through the air and involves close personal contact with an infected individual, surfaces or objects which they have been in contact. As the virus is highly contagious, it will remain active in the air and on these surfaces for up to two hours. It has been noted that up to 90% of people without immunity sharing a house with an infected individual will become infected (Schneider-Schaulies & Meulen 2000). Infected individuals can transmit the MV from four days prior to the onset of the rash to four days after the rash erupts. Studies also show the MV can be inactivated by heat, light, acidic pH, ether, and trypsin (Topley & Wilson 2005).
The virus replicates in the respiratory tract and then reaches local lymphoid tissue, producing primary viremia. Lymphoid tissues such as the thymus, spleen, and tonsils are normal sites of replication. Following replication within the lymphoid tissue, the MV spreads to other organs including the skin, kidney, lungs, liver and gastrointestinal tract known as secondary viremia. The MV replicates in epithelial and endothelial cells and is accompanied by vascular dilation, increased vascular permability, mononuclear cell infiltration and infection of surrounding tissue (Topley & Wilson 2005).
Small white spots develop inside the buccal cavity known as Koplik’s spots (fig 3a) due to nectrotic infection of the submucous glands, at this stage the individual is highly contagious and giant cells are present in the sputum and other secretions this occurs just prior to development of the typical rash. Each of these signs is a typical characteristic of measles infection the rash then erupts, usually on the forehead, face and upper neck. The rash then spreads to cover the entire body over the next 3 days, lasts for about six days before it begins to disperse, this typical presentation is seen in figure 3b. This rash is said to occur due to vascular congestion epithelial necrosis and oedema. The entire course of uncomplicated measles, from late prodrome to resolution of fever and rash, is approximately 7-10 days.
Fig 3. Characteristics of Measles infection (accessed from google images)
Complications arising from measles infection result mainly from opportunistic secondary infections due to the immunosuppression induced by MV. The depression of the immune response may last up to 6 months (Kerdiles et al 2006). Complications are more common in children under the age of five, or adults over the age of 20 and occur in individuals who arepoorly nourished, especially those insufficient in vitamin A, or individuals with existing immunodeficiency such as HIV/AIDS. Diarrhoea and severe dehydration is not uncommon in developing countries where secondary infection is likely and worsens their individual’s nutritional status; this along with lack of substantial vitamin A may lead to post-measles blindness. Ear infections and pneumonia may also occur which will require antibiotics to treat the imposing infectious agent. Treatment of giant cell pneumonia is a very protracted and causes the majority of measles related deaths.
However, more serious complications like encephalitis and persistent brain inflammation known as subacute sclerosing panencephalitis (SSPE) also occur though these are rare. SSPE will be discussed further on in this text. Measles infection during pregnancy may induce spontaneous abortion or still births other reports have stated measles infection during pregnancy may produce infants with a low birth weight or congenital malformaty (Schneider-Schaulies & Meulen 2000). Administration of antimeasles gammaglobulin less than three days after exposure may protect from infection this is discussed further in vaccination section.
Acute encephalitis results in death in approximately 15% of patients who develop it (Schneider-Schaulies & Meulen 2000). Development usually occurs eight days after onset of the rash, symptoms of this can include recurrence of a high fever, persistent headache, vomiting, drowsiness, seizures and coma. Measles Inclusion Body Encephalitis occurs only in the immunocompromised e.g. individuals with leukaemia present without rash as no immune response was elicited and is often confused with SSPE. Symptoms include seizures stupor or coma which is dependent on localisation of the disease within the CNS. This type of encephalitis has no antibodies detectable in the CSF (Schneider-Schaulies & Meulen 2000).
Infection and spread
MV replication involves the transcription of viral RNA to give + sense mRNA before this can be translated. The F protein facilitates fusion with the plasma membrane. Viral multiplication occurs in the cytoplasm, using the RNA polymerase and RNA modification enzymes packaged in the virus and use the nucleoplasmid as a template to transcribe viral mRNAs; theseare capped, methylated and polyadenylated translated and packed into the new virues and bud out through the cell plasma membrane.
The non structural proteins C and V also play an important role in replication of the virus, this has be confirmed by in vitro studies, results of studies with animal models show that these proteins are also important for the virulence of the virus. They have also been investigated for their ability to produce IFN responses; C protein was shown to inhibit this (Kerdiles et al 2006).
MV interaction with the immune system involves studying measles infection in humans, naturally and experimentally infected rhesus monkeys, cotton rats and transgenic mice and also some in vitro models (Griffin 2010). It is well known that the primary target for the MV is the monocyte and primarily causes the viremia during infection with accompanied leukopenia.
Three cellular receptors for MV are recognized: the low affinity membrane co-factor protein CD46, present on all nucleated cells was the first receptor identified for the MV (Topley & Wilson 2005). CD46 is the natural binding site for C3b/C4b complement components however; it also binds to the viral hemagglutinin (H) protein of the measles virus.
The second receptor; higher affinity signaling lymphocyte activation molecule (SLAM ? CD150), a glycoprotein belonging to the immunoglobulin superfamily is present on subsets of lymphocytes, thymocytes, macrophages, and DCs; and an unidentified receptor present on ciliated columnar respiratory epithelial cells (Griffin 2010).
Recent studies have questioned the role of CD46 in vivo. This is confirmed as all viral strains tested preferentially bind CD150, therefore CD150 is the primary determinant of MV tropism (Griffin 2010). MV infections usually produce very distinctive cytopathic effects enabling formation of multinucleated giant cells. Binding of H protein to both CD46 and CD150 downregulate receptor expression; this may lead to activation of complement against uninfected lymphocytes, thus contributing to the associated leukopenia. This profound suppression of cell-mediated immunity was confirmed by Karp et al in 1996. Conversly interaction of H protein with TLR2 on surface of monocyte will stimulate IL-6 and increase CD150.
This process also results in decreased IL-12 production from infected monocytes which may be a result of the reduction of IFN-? produced by T cells. The nucleocapsid protein (N) also reduces the release of IL-12 from monocytes, with resultant reduction in T cell proliferation which may lead to cellular apoptosis (Topley & Wilson 2005). IFN-? also aids in the production of nitric oxide, though with down regulation of CD46 will alter the immune response to other intracellular pathogens e.g. mycobacteria. Therefore, CD46 as receptor in MV infection may disturb different aspect of the immune response. Downregulation of CD150 after infection may impair the Th1 response towards other pathogens due to the decrease in IFN-?.
Cytokines and chemokines produced during infection include IL-8 which is increase in early infection. IL-2, IFN-?, are increased during the corresponding rash. In vitro systems have shown there is reduced IL-2 production during the inital stage of infection, Griffin et al shown that introduction of recombinant IL-2 along with neutralisation of high IL-4 restores lymphocyte proliferation (Topley & Wilson 2005).
The rash is associated with MV infection is due to the infiltration of CD4+ and CD8+ T cells into the site of replication, with the CD8+ response occurring more rapidly than CD4+ which is more protracted. IgM response to infection occurs alongside appearance of the rash, to which serological detection is diagnostic. Increased MV specific IgG follows recovery from infection conferring lifelong immunity, notably in vitro infection of B cells reduces Immunoglobulin production, through binding of N protein to activated cells however in vivo studies show no B cell defect (Niewiesk et al 2000). After resolution of the rash regulatory CD4+ cells produce IL-4, IL-10 and IL-13 (Griffin 2010). Changes to the cytokine profile seen with CD150 interactions may show that infection starts with a Th1 response and then converts to a regulatory Th2 response in later infection resulting in delayed hypersensitivy response.
Diagnosis & Treatment
Diagnosis of measles is based upon the individuals’ history and clinical presentation, with appearance of Koplik spots and typical rash being diagnostic. However, laboratory methods may be required for more complicated cases e.g. in the case of modified or atypical measles. The virus is detectable by a number of different methodologies these include direct microscopy, immunofluorescence of nasopharyngeal secretions or urine, viral cultures and electron microscopy can all provide diagnosis. Though measles is best confirmed by serological detection of; IgM antibody against the virus, in the acute phase and IgG in the convalescent phase of disease using ELISA.
Prevention of disease by administration of vaccine should always primary goal rather than treatment of disease, as the vaccine is cheap, safe, and effective. Adequate nutrition, fluid replacement and appropriate use of antibiotic if required is all that can be provided to treat measles infection though its recommended that all children in developing countries diagnosed with measles should receive treatment with two doses of vitamin A, given 24 hours apart should be provided to individuals in developing countries prevent permanent loss of vision, provision of this supplement has shown to reduce the number of deaths from measles by 50% (WHO factsheet 2009).
Vaccination is the greatest success in Immunology; historically it all started with Jenner, cowpox and smallpox which led to production of a vaccine. However, now in the 21st century there are a multitude of vaccinations available. The WHO classified smallpox as being eradicated worldwide in 1980 and publish lists of prevalence of those diseases which they continue to strive to eliminate worldwide.
The first measles vaccines were licensed in 1963. This included an inactivated vaccine and a live attenuated vaccine known as the Edmonston B Strain. The inactivated vaccine was withdrawn as it did not produce an immunogenic response and therefore did not provide immunity to the disease, those immunised with this vaccine may have later developed atypical measles if infected with the wild type virus. Atypical measles progresses similarly to measles though individuals will also experience headaches and abdominal pain with the rash beginning on the extremities and spreading over the body. It has been proposed the inactivated vaccine did not produce antibodies to the F protein and thus was unable to prevent its spread (Schneider-Schaulies & Meulen 2000).
Modified measles is another form of the disease which occurs in partially immunised children or individuals who have received immune serum globulin and symptoms appear much milder than seen in acute measles (Schneider-Schaulies & Meulen 2000).
The original Edmonston B vaccine was able to seroconvert 95% of recipients however it was withdrawn in 1975 as it produced a mild form of measles in up to 10% of those vaccinated, to reduce the side effects gammaglobulin was administered. Thus, further live attenuated vaccines were sought including the Schwarz strain in 1965, and the Edmonston-Enders strain produced by passage in chicken cells was licensed in 1968, which caused fewer reactions than the original Edmonston B vaccine (Undergraduate Notes).
The vaccine was combined with mumps and rubella vaccines and is licensed in 1971 as MMR (Undergraduate Notes). Furthermore, two doses of the vaccine was recommended to ensure immunity in 1989, as about 15% of vaccinated children fail to develop immunity from the first dose (WHO factsheet 2009). Varicella vaccine may also be combined and administered as MMRV, this format of vaccination was licensed in 2005. These vaccines are now supplied lyophylised and contain a small amount of human albumin, neomycin, sorbitol, and gelatine and are reconstituted prior to use. Clinical study of 284 triple seronegative children, 11 months to 7 years of age, demonstrated high immunogenic capability of the vaccine as it induced hemagglutination-inhibition antibodies in 95% of individuals for the measles vaccine thus conferring its effectiveness (MMR vaccine 2010).
However, dispute that the vaccine causes autism first arose when Wakefield et al reported this in 1998 which may have reduced uptake of vaccine in theUKfor a period time before these claims were discredited by epidemiological studies which consistently found no evidence of a link between the MMR vaccine and autism. Vaccination rates in theEnglandhave increased from the 80% low in 2003-4 but are still below the 95% level recommended by the WHO to ensure herd immunity (HPA), notably the number of measles cases recorded in 2010 has decreased with improved uptake of the vaccination (HPA2).
Global cooperation between a number of organisations has also ensured that 83% children received their first measles vaccine by the age of 1, up from 72% in 2000 (WHO factsheet 2009), and will work together in advancing the global measles strategy. In countries where measles has been largely eliminated, cases imported from other countries remain an important source of infection.
Subacute sclerosing panencephalitis(SSPE)
SSPE is an extremely rare degenerative condition of the brain caused by the reactivation of the measles virus after an interval of 6-8 years though incidences have also occurred almost 30 years from primary infection. The disorder is usually fatal and effects males more often than females, though incidence of SSPE is very low 1 case per 100 000(Schneider-Schaulies & Meulen 2000). Most individuals with SSPE contracted the MV before the age of two, symptoms usually are slow and progressive, and begin with deterioration in the individuals’ mental faculty and individuals may experience hallucinations. Symptoms may not be recognised until further neurological or motor symptoms appear such as convulsions, dyspraxia, aphasia and other abnormal uncontrollable muscle movements. Visual disturbances may also occur if the virus invades the retina leading to complete blindness. The disease is nearly always fatal within 1 to 3 years.
Diagnosis is made on the clinical presentation and confirmation by a high titre of antibody to the MV (Schneider-Schaulies & Meulen 2000). Investigations would include electroencephalogram (EEG), and computerised tomography (CT) to shown scarring of the brain and neuronal activity. There is no treatment available for those afflicted with SSPE; anticonvulsants such as Phenobarbital, valproic acid and others may be prescribed to control seizures. Although this disease is very severe and rare the final cause of death is usually pneumonia, the pneumonia results from extreme muscle weakness. With adequate vaccination cases of SSPE have also declined.
Topley & Wilsons Microbiology & Microbial Infections – Immunology 10th edt. Published by Edward Arnold Ltd. 2005 Chapter 39 Acquired immunodeficiencies pgs 803-806
Morgan EM & Rapp F. Measles Virus and Its Associated Diseases. Bacteriological reviews Sept. 1977, Vol. 41, No. 3 pgs. 636-666
Principles and Practice of Clinical Virology 4th edt. Published by John Wiley & sons Ltd. 2000 chapter 11 Measles by Schneider-Schaulies & Meulen pgs 357-385
GriffinDE. Measles virus-induced suppression of immune responses. Immunological Reviews 2010 Vol. 236: 176–189
McChesneyMB, Oldstone MBA, Fujinami RS et al Virus Induced Immunosuppression: Infection of peripheral blood mononuclear cells and suppression of Immunoglobulin synthesis during natural measles virus infection in rhesus monkeys. Journal of infectious diseases 1989 159:4 757-760
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World Health Organisation. Mealses factsheet no 286 2009
Measles Initiative UN: Statement on Eradication by Kofi Annan 2011 http://www.measlesinitiative.org/
Figure 3 images obtained from http://www.google.co.uk/images
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GriffinDE, Moench TR et al. Peripheral blood mononuclear cells during natural measles infection; cell surface phenotypes and evidence for activation clinical immunology and immunopathology 1986 40 305-312
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Information from Undergraduate notes 2008
MMR vaccine kit insert from Merck & Co Inc.Whitehouse Station NJ,USApublished 2010
Health Protection Agency. (HPA1) Completed primary course at two years of age: Englandand Wales, 1966-1977, Englandonly 1978 onwards. http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733819251.
Health Protection Agency. (HPA2) Confirmed cases of measles, mumps and rubella 1996-2009. http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733833790