Author manuscript Chapter 26 in “Human Respiratory Viral Infections” Edited by Sunit K. Singh, 2014 CRC Press, Taylor & Francis Group, Boca Raton (FL), USA
Measles virus: a respiratory virus causing systemic disease Rory D de Vries & Rik L de Swart* Department Viroscience, Erasmus MC, Rotterdam, the Netherlands * Corresponding author: Dr. Rik L. de Swart, Department Viroscience, Postgraduate School Molecular Medicine, Erasmus MC, Rotterdam, the Netherlands, PO Box 2040, 3000 CA Rotterdam, The Netherlands, E-mail address:
[email protected]; telephone: +31 10 7044280; fax: +31 10 7044760. INTRODUCTION Measles remains an important vaccine-preventable cause of morbidity and mortality. The causative agent, measles virus (MV), is one of the most contagious human viruses known, and is transmitted via aerosols or direct contact with contaminated respiratory secretions. However, the virus causes a systemic disease. Clinical signs appear approximately two weeks after primary infection and include fever, rash, cough, coryza and conjunctivitis.1 While significant progress has been made in global control programs, 139,000 deaths were still attributed to measles in 2010.2 Over the last decade, identification of new cellular receptors and studies in animal models with recombinant (r) viruses have challenged the historic concepts of measles pathogenesis. Here we provide an overview of our current understanding of MV entry, dissemination and transmission to the next host. Furthermore, we will discuss the main cause of measles-associated morbidity and mortality, the transient but profound immune suppression. Finally, this chapter includes a brief discussion on measles vaccination and eradication.
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MEASLES Pathogen MV belongs to the family Paramyxoviridae, genus Morbillivirus, and is the only virus within this genus that targets primates as its natural host. Virus particles are pleiomorphic and average in size from 100 – 300 nm.1 The viral genome consists of a single-stranded RNA molecule of negative polarity, typically 15,894 nucleotides (nt) in length, consisting of 6 genes that encode 8 proteins (Figure 1A). The genome is contained in a helical nucleocapsid, which is surrounded by a lipid bilayer.3 This envelope is derived from the membrane of the infected cell during budding.4 Genes are transcribed by a start-stop mechanism from a single promoter at the 3’ end of the genome leading to a so-called transcription gradient, which means that mRNA transcribed from the genes closest to the 3’ end are present in greater abundance than those transcribed from the genes at the 5’ end.5,6 This is due to the chance that between each open reading frame (ORF) the virus-associated RNA-dependent RNA-polymerase (RdRp) may dissociate from the genome, and thus has to re-initiate transcription at the 3’ end. The nucleoprotein (N) mRNA is produced first, since it is at the promoter-proximal position of the genome. The main function of the N protein is to encapsidate the genomic RNA. Since one N protein covers 6 nt, the genome lengths of morbilliviruses obey the “rule of six” (i.e. the genome length must be a multiple of six nt).5 The second gene in the morbillivirus genome is the phosphoprotein (P) gene, which encodes two different mRNAs and three proteins: P, V and C. The P protein is a co-factor of the RdRp,7 essential in transcription and replication. The C and V proteins are either translated from an overlapping reading frame or as co-transcriptionally edited products of the P mRNA.8,9 The V protein is important in immune inhibition, potentially interfering with the type 1 interferon pathway by binding to DBB1, mda-5, STAT1 and STAT2.10-15 The C protein has been suggested to modulate the viral polymerase activity and play a role in interference with the innate immune system.16,17 An rMV defective for C proved to be growth-defective in peripheral blood mononuclear cells (PBMC) and less virulent in vivo.18,19 The matrix (M) protein is assumed to associate with the inner leaflet of the virus envelope (Figure 1B).20,21 However, a recent publication using electron cryotomography revealed that in MV particles the M protein coats the N-coated viral RNA, rather than localizing to the envelope (Figure 1C).22 The M protein has an important role in the morphogenesis of viral particles,23 and may be the driving force in viral budding. M is thought to interact with both
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the N protein24 and the cytoplasmic tails of the viral envelope glycoproteins to ensure incorporation of the viral genome into nascent virions.25,26 The mRNAs encoding the two viral transmembrane glycoproteins, the fusion (F) and hemagglutinin (H) proteins, are transcribed after M. The F glycoprotein mediates membrane fusion, either between the virus particle and a host cell (virus-to-cell fusion) or between two adjacent host cells (cell-to-cell fusion). The H glycoprotein mediates attachment of the viral particle to host cell receptors. The F glycoproteins form trimers while H is present as a dimer of dimers, which interact to form the fusion complex.27 Upon binding the cellular receptor, the H glycoprotein undergoes a conformational change and triggers the fusion activity of the F glycoprotein.28,29 Therefore, the combination of the F and H glycoproteins is critical for viral entry and cell-to-cell spread. The transcription unit encoding the large (L) protein mRNA is located at the 5’ end of the genome and accounts for more than 40% of the genome length. The L protein acts both as a transcriptase and as a replicase, in a complex with P.7,30-32 Virus life cycle A schematic representation of the morbillivirus life-cycle is shown in Figure 1D. To initiate infection of a target cell, the H glycoprotein interacts with an entry receptor present on the cell surface. After virus binding and fusion of the viral membrane with that of the host cell, the minimal unit of infectivity, the ribonucleoprotein (RNP) complex, is released into the cytoplasm. The RNP is comprised of the viral genome associated with the N, P and L proteins. In the cytoplasm, the RdRp is responsible for primary transcription during the first 6 hours post infection (h.p.i.). In the second phase of infection (6 – 12 h.p.i.) newly synthesized RdRp leads to an exponential increase in mRNA synthesis. In the third phase of infection (12 – 24 h.p.i.) the emphasis shifts from transcription to genome replication: RdRp switches from functioning as a transcriptase to functioning as a replicase. During the viral replication cycle, the F and H glycoproteins are modified in the Golgi apparatus and translocated to the cell membrane.33 The presence of these glycoproteins at the cell membrane can generate syncytia or multi-nucleated giant cells, which can be seen in the lungs or lymphoid tissues of MV-infected hosts. Newly formed RNP associates with the M protein, which is recruited to the plasma membrane. Here, new viral particles are generated by budding from lipid rafts. The interaction between the M protein and the cytoplasmic tails of the trans-membrane glycoproteins ensures that new viral particles have an envelope
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containing F and H glycoproteins on its surface. The M protein and the RNP are incorporated into the newly formed virus particles. Clinical features After initial infection via aerosol inhalation, MV replicates in the lymphoid tissues of the respiratory tract. After a relatively long incubation phase, during which no clinical signs are observed, patients enter a prodromal phase where they develop fever and upper respiratory tract symptoms. A few days later Koplik’s spots, the pathognomonic feature of MV infection, appear on the buccal mucosa.1 The hallmark of measles is a maculopapular rash that appears around 14 days post infection (d.p.i.),34 starting behind the ears and eventually covering the entire body. Within a few days symptoms usually start to subside, and in absence of further complications patients recover rapidly (Figure 2). Measles is associated with immune suppression, leading to an increased susceptibility to opportunistic infections. This is the primary reason why a significant percentage of measles patients develop complications, resulting in a plethora of clinical symptoms.35-38 For instance, bacterial pneumonia is a common complication and a major cause of measles-associated deaths.39 In addition, there are rare but severe central nervous system complications associated with measles, including acute post-infection measles encephalitis (APME), measles inclusion body encephalitis (MIBE) and subacute sclerosing pan encephalitis (SSPE).40-43 The mortality due to measles is directly associated with the socio-economic status of the infected population. Mortality rates may reach 25% in refugee camps or overcrowded populations, 5 – 10% in developing countries, but is usually less than 0.1% in industrialized countries.44,45 Epidemiology MV is highly contagious, with an estimated basic reproductive number (R0) or average number of secondary cases produced by an infectious individual in a fully susceptible population of 12 – 18.44 Many of the features of MV transmission have been deduced from studies performed by Peter Panum, who investigated a measles epidemic in the Faro Islands in 1846. He estimated that MV-infected individuals are capable of transmitting virus to susceptible contacts for a total of 7 – 9 days, starting several days before until few days after onset of rash.46 In previously unexposed, immunologically naive populations, MV infects individuals of all age groups. However, in populations where measles has previously been endemic older members of the community are generally immune, and measles becomes a childhood disease.1 Maintenance of MV in a population requires a continuous supply of susceptible individuals. If the population is too small, endemic transmission cannot be
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maintained.47 A population size of at least 250,000 – 500,000 is necessary to establish measles as an endemic disease.48 MV is highly susceptible to neutralizing antibodies, protecting infants during their first months of life. Since women with vaccine-induced immunity usually have lower MV-specific antibody levels than women with naturally acquired immunity, their infants receive lower levels of maternal antibodies and become susceptible at a younger age.49 An important consequence of the high transmissibility of MV is that vaccination coverage of >95% is required to eliminate endemic transmission.50,51 Immunization directly alters the epidemiology of measles and the kinetics of MV transmission. If vaccination coverage is high, but
