MEASLES VIRUS

Table of contents :

  • Epidemiology
  • Genomics
  • Proteomics
  • Transmission
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Prevention
  • Web resources
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    Epidemiology : epidemics every 2-3 yrs. at late Winter; usually within age 15; 2002 incidence : 30 millions. Deaths :

    Deaths from the contagious disease which can be prevented by vaccination have already fallen by 39% since 1999 (873,000 deaths) to 2003 (530,000 deaths), though 2004 figures are not in yet. The world is "on target" to halve global deaths from measles by the end of 2005. Only a decade ago, measles killed millions of children each year, and left many with life-long disabilities such as blindness and brain damage. Africa remains the hardest-hit continent, but even there, the number of cases has fallen 46% due to mass vaccinations. WHO and UN campaign is targeting 45 countries, mostly in sub-Saharan African and south Asia, where measles immunisation coverage averages only 60%. The focus now is to increase support to the large priority countries -- Nigeria, India and Pakistan. About 50% of all measles deaths last year occurred in the 3 countries. Nigeria, India and Pakistan -- where the crippling polio virus is also taking a toll despite a global eradication campaign -- lack strong health care systems and routine vaccine coverage. The likely next goal would be to reduce mortality by 90% by 2010, compared with 1999. It costs around 25 cents to immunize a youngster. Because this is beyond the budget of many poor countries, they have been helped by the U.N. campaign. The campaign aims to ensure 90% of children are immunized before they are 9 months old, with booster vaccinations every three or four years until age 14. The program has reached >150 million children since it was launched in 2001. Late in 2004, > 95% of children in the African nation of Togo received vaccines to prevent measles and polio, mosquito nets to stop the spread of malaria, and tablets against worms. Despite the advances, millions of children remain at risk from measles. Malnourished and unimmunized children under age 5, especially babies, are particularly vulnerable Genomics : for purposes of molecular epidemiology 8 clades of measles virus strains have been defined (A to G), and within these clades 22 distinct genotypes have been recognised (some of which appear now to be extinct) on the basis of the nucleotide sequence of the most variable gene, the SH gene. The different lineages are useful properties for establishing links between outbreaks and routes of transmission of the virus, but there is no clear association of the different lineages with different clinical symptoms
    Proteomics : Transmission : inhalatory or conjunctival route
    Pathogenesis : MV establishes a systemic infection, which starts in the respiratory tract, spreads to the local lymphatic tissues and disseminates by cell-associated viraemia to a wide range of organs and tissues. The infection normally induces an efficient MV-specific immune response which eliminates the infection and confers life-long protection against measles. At the same time, however, MV infection leads to immunosuppression, which favours secondary infections. These opportunistic infections are the major cause of death among measles patients. Leukocytes thus act both as vectors for dissemination of the virus throughout the body and as targets for the immunosuppresive effects of MVref1, ref2,Schneider-Schaulies, S. & ter Meulen, V (1999). Pathogenic aspects of measles virus infections. Archives of Virology Supplement 15, 139–158. MV can cause apoptosisref1, ref2, ref3, ref4, inhibit the lymphoproliferative responseref, and induce interferons and other cytokinesref1, ref2. Infected PBMC upregulate NF-kB p52 subunit (which homodimers that are considered to be mainly transcriptionally repressiveref), the anti-apoptotic Bcl-3 (which binds p50 and p52 homodimersref converting the latter from a repressive to a transactivating transcription factorref. Furthermore, binding of Bcl-3 to p52 or p50 homodimers may free NF-B sites on the DNA from the repressive homodimers and thus provide access for transactivating NF-B dimers, for instance the p50p65 heterodimerref. Bcl-3 also counteracts apoptosisref and recently Bcl-3 was found to protect activated T cells against apoptosis by inhibiting activation-induced cell deathref. Apoptosis of infected cells may inhibit viral multiplication and many viruses appear to have developed anti-apoptotic countermeasuresref. It remains to be determined whether the MV-induced Bcl-3 upregulation protects the virus against apoptosis of its host cell. The Bcl-3 and NF-B p52 genes were also found to be upregulated by vaccinia virus and HPV-16, respectivelyref1, ref2), IRF7, chaperones, transcription factors and other proteins of the endoplasmic reticulum stress response, the pro-apoptotic and growth arrest-inducing CHOP/GADD153 proteinref. The ER stress response can play a key role in induction of apoptosis, and increasing evidence also points to a role in the IFN responseref. MV infection induces the ER stress response due to the flux of viral glycoproteins through the ER. The migration of MV glycoproteins towards the cell surface is slow and incompleteref1, ref2, ref3. In pulse–chase experiments, MV glycoproteins were associated with ER chaperones for prolonged intervalsref, indicating that folding of the MV glycoproteins into their correct conformation is an extensive task for the ER folding machinery. ERp57 is a protein disulphide isomerase, which forms complexes with the ER chaperones calreticulin and calnexin. These complexes are believed to mediate folding of nascent glycoproteins in the ERref1, ref2. Induction of these three genes as well as that of GRP78, which is also an ER chaperone, improves the capacity of the ER to handle incoming viral glycoproteins, thus protecting the cell against protein aggregation. Herp is a recently discovered stress-induced integral protein of the ER membrane. Herp has a ubiquitin-like domain, but the function of Herp and its role in the ER stress response remains to be determinedref. Activating transcription factor 4 (ATF-4), also called cAMP response element binding protein 2 (CREB-2), and transcription factor II-I (TFII-I) are both involved in the activation of promotors of genes upregulated by ER stressref1, ref2. ATF-4 was also found to be upregulated by other viruses in microarray studiesref1, ref2. The CHOP/GADD153 protein has been reported to block transition from the G1 to the S phase of the cell cycleref. Arrest of lymphocytes in the G0 or G1 phase of the cell cycle is believed to be an important mechanism behind the reduced lymphoproliferative response and the immunosuppression in patients with measlesref1, ref2, ref3. Thus, although purely speculative, it is possible that the ER stress response, through the induction of CHOP/GADD153, is involved in the MV-induced reduction of lymphocyte proliferation. MV-induced upregulation of 2',5'-oligoadenylate synthetase (2-5A) and ICAM-1 has previously been describedref1, ref2. Membrane protein E16 (CD98 light chain) is an amino acid transporter, which is disulphide-linked to the 4F2 (CD98 heavy chain) glycoproteinref. Interestingly, the CD98 heavy chain appears to modulate cell fusion by Newcastle disease virus and human parainfluenza virus type 2ref. E16 was also upregulated by cytomegalovirusref. A strong and broad IFN response comprising several IFN subtypes requires the positive feedback regulation of IRF3 and 7 in virus-infected cells. IRF-3 is constitutively expressed and activated post-translationally, whereas IRF-7 is regulated at the transcriptional levelref. Servant et al.ref recently demonstrated MV-induced IRF-3 activation, and in the present study we demonstrate MV-induced upregulation of the IRF-7 gene. Several studies have shown that MV strains differ in their IFN-inducing properties, and it has been suggested that virulent MVs can inhibit the induction of type 1 IFNref1, ref2, ref3. Naniche et al.ref recently reported that wild-type isolates, which had been isolated and passaged on lymphoid cells, were much weaker inducers of type 1 IFN than the Edmonston strain and the Edmonston-derived Moraten vaccine strain. The present study is in agreement with this finding, since the wild-type MV isolate was a weaker inducer of the IFN-a and -b genes than the Edmonston strain. However, this difference in induction of host cell genes was not confined to the type 1 IFN genes. The Edmonston strain and the DK96A1 wild-type appeared to upregulate the same cellular genes, but the wild-type isolate was a weaker inducer of almost all the studied MV-induced genes than the Edmonston strain. In the present study, this difference could be explained by a better in vitro growth of the Edmonston than the wild-type isolate. This is the first large-scale study of the role of MV infection in host cell gene expression. As a starting point, we chose to examine non-selected primary PBMCs and to minimize the influence of non-viral factors by using viruses (and mock material) passed on PBMC cultures. Since MV does not grow to high titres in PBMC cultures, only a low m.o.i. could be obtained. The PBMCs were analysed when most cells were infected, but at a time where cells at all stages of infection were present in the culture. Future studies may preferably be carried out with high-titre virus stocks in order to establish more synchronized infections, which can be assayed at different time points. More pronounced modulation of the expression levels than seen in the present study are also likely to be obtained with homogeneous cell populations such as cell lines or selected PBMC subpopulations. Microarray-based analyses of virus-induced modulation of host cell gene expression have been reported for several other virusesref1, ref2, ref3, ref4. The number of genes found to be differentially expressed in virus-infected cells was highly variable, but most of these studies identified a higher number of genes than the present study, and both up- and downregulated genes were found. Several factors including characteristics of the individual viruses and the experimental strategies are likely to influence the number of differentially regulated genes that can be identified. The use of mitogen-stimulated PBMCs may be an important factor, since PHA-L treatment is likely to induce a wide range of cellular genes. Virus-induced downregulating signals may be overridden and virus-induced upregulations may to a large extent drown in PHA-L-stimulated PBMCs.
    => measles / morbilli / rubeola (a.k.a. morbillo in Italy) : the incubation period from exposure to rash onset for measles is approximately 10 days (range 7-18 days); on rare occasions the incubation period can be as long as 19-21 days => prodromic rash The infectious period for measles is from 4 days before to 4 days after onset of rash.
    Complications : Globally 1 every 800 die and 1 every 500 has serious brain damage. Permanent immunity.
    Vaccination was thought to provide life-long immunity similar to natural infection. Immunity against measles was supposedly maintained in adult populations by subclinical re-infection. Serological confirmation of subclinical re-infection was obtained by pre-exposure in household-exposed parents who developed asymptomatic secondary immune responses with a concomitant increase in specific IgG neutralizing test antibodies and haemagglutination inhibition titresref1, ref2. IgM antibodies against measles virus were detected in 10 (23%) of 44 bus-tour participants who had been exposed to measles during a 3-day trip and none developed typical measles symptoms. All cases were defined by serological evidenceref. Measles virus was isolated from PBMC in mild cases of measles where the patient had previously been immunizedref. Recently, measles virus was isolated in a case of infection by household contact without any symptomsref. The index case was identified as a secondary measles infection with positive isolation of measles virus and serological evidence. Measles virus was isolated from urine of the patient’s mother without IgM antibodies or a booster of neutralizing antibodies and the genomic sequence of the isolated virus was identified as similar to that obtained from the index case. In our previous examination in paediatric populations, the measles virus genome was detected in 36 of 78 individuals (40 of 159 samples) who were immunized more than 2 months before, and was identified as a circulating wild strain in all cases. Among 13 healthy individuals more than 2 months after natural infection, the measles virus genome was detected in six (seven out of 26 samples). There was no close relationship between the PCR positivity and the period since immunization or natural infection. PCR-positive samples were obtained from April 1993 to January 1995, in accordance with regional measles outbreaks. Thus, asymptomatic measles infections are probably very common manifestations of measles during outbreaks in highly immune populationsref. Following this line of research, we examined PBMC obtained from healthy adults for the measles virus genome but failed to detect the genome. Remaining portions of bone-marrow aspirate samples were examined after cytological examination, bacterial culture and so on. Measles virus genome was detected in 17 of 179 individuals (9.5%) by RT–PCR and ethidium bromide staining. Through dot-slot hybridization, it was detected in 28 of 179 individuals (15.6%). There was no relationship between the detection rate of measles virus genome and haematological malignant disease. In patients with malignant lymphoma and acute leukaemia, the detection rate of measles virus genome was slightly higher than in those with non-malignant haematological diseases, reflecting immunosuppression due to basic illness or chemotherapy. Subclinical infection was confirmed in adulthood and the detection of measles virus genome was not related to the illness. Recently, it was hypothesized that some non-infectious diseases, inflammatory bowel diseases and autistic developmental disorders, might be related to the MMR vaccine. Measles virus genome has been detected in PBMC of patients with autoimmune hepatitis, inflammatory bowel diseases, intractable convulsion, and autismref1, ref2, ref3, ref4. However, there was no evidence of the presence of measles virus using N gene RT–PCRref and, epidemiologically, no supportive evidence was reportedref. The pathological relationship of the persistence of measles virus to the onset of diseases is still controversial. Measles virus genome RNA was detected in autopsy brain material with high positivity and some were identified as current strains by sequence analysisref. Asymptomatic measles infections occur even in the adult population with unexpectedly high frequency, and this supports the preservation of measles immunity. The presence of the measles virus genome is not directly connected to the pathogenesis of illness but might be a symptomatic infection, with no relationship between the detection of the measles virus genome and specific diseasesref.
    Laboratory examinations : Prevention : attenuated vaccine. There are conflicting results regarding the prevention of secondary cases (measles transmission and clinical infection) by post-exposure immunisation of  despite rapid diagnosis : Differences might be due to differences in timing of administration, vaccine formulation or interpretation of observations made on small numbers of cases. Vaccination rates in some states and cities have dropped to levels that would allow an outbreak of measles to be sustained if a case gets into the community. This could have severe consequences as evidenced by measles outbreaks in the US between 1989 and 1991, mainly among unvaccinated, preschool-aged children that infected > 55 000 people and resulted in 123 deaths. MMR vaccination rates in the UK have dropped to the lowest level in at least 8 years, primarily due to unfounded concerns by parents that the vaccine is linked to autism. The lowered immunization rates already appear to be leading to increases of mumps, rubella, and measles. In Scottish children under age 15, suspected cases of measles have jumped by 18% in the last 18 months -- and rubella by 22% and mumps by 27%. Most of these cases will turn out to be due to other causes but the trend does suggest the diseases are on the increase. The current rate of MMR vaccine coverage in the United Kingdom stands at about 86%, and in some areas the coverage rate has dropped as low as 61%. Health officials think a vaccine coverage rate of about 95% is necessary to prevent outbreaks and anything below 90% could allow outbreaks to flourish. In the US, MMR vaccine coverage is about 91.6%, but several areas have rates of only 87% or lower, including Arizona (except for Maricopa County), Montana, Oklahoma, Oregon, Shelby County Tennessee, Houston Texas, and parts of Colorado (close to 20 percent of kids are not immunized). Some states have vaccination rates below the 90% mark, including Alaska, most of California, Idaho, Kentucky, Louisiana, Nevada, Washington, and Wyoming. The numbers are averages for these whole states, so there could be pockets where the coverage rates are much lower. Even if some local populations have only 50% immunization coverage, they could be overlooked within an average of 91% for the whole state. Keeping the immunization coverage uniformly high is essential because an increasing number of unvaccinated people makes it easier for a case of measles to take hold and, in turn, boost the likelihood of spreading the disease to vaccinated individuals -- because no vaccine confers 100% protection. The real threat is the same thing that has driven down immunization rates in the United Kingdom and Japan, and that is parental resistance to having their children immunized. In the Marshall Islands measles outbreak that began in Summer 2003 and has resulted in 752 cases and 3 deaths, the vaccination coverage was about 75%. This is of concern because people infected in that outbreak are known to have traveled into the United States. Mexico also recently had measles cases imported from Asia, and this could easily spread across the border into the USA
    Between 2000 and June, 2003, 82.1 million children were targeted for vaccination during initial supplemental immunisation activities (SIA) in 12 countries and follow-up SIA in 7 countries. The average decline in the number of reported measles cases was 91%. In 17 of the 19 countries, measles case-based surveillance confirmed that transmission of measles virus, and therefore measles deaths, had been reduced to low or very low rates. The total estimated number of deaths averted in the year 2003 was 90,043. Between 2000 and 2003 in the African Region as a whole, the percentage decline in annual measles deaths was around 20% (90043 of 454000)ref.
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