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Infectious Disease Review into Measles
Measles is a systemic infection caused by the measles virus which is a part of the Paramyxoviridae family and the Morbillivirus genus (Hussein, 2014). The infection is characterised by a fever of around 38.3oC, a generalized maculopapular rash (which lasts for 3 days or more), a persistent cough and possibly conjunctivitis (MacFadden & Gold, 2014). The virus has only a single serotype but can be classified into different genotypes dependant on its specific genetic sequencing (Furuse & Oshitani, 2017). There are 23 genotypes of the virus according to the world health organisation (WHO) which classifies them into clades designated A-H. The types observed in the last four decades are: type A (associated with sporadic infections), type B (African related) type D (outbreaks in India, the United States, Japan and Pakistan) and type H (China related infections) (Wei et al, 2012). In the UK, the genotype associated with endemic transmission is D4. However, there are numerous genotypes that are suspected to be present through importation (see table 1) (Rota et al., 2011).
The virus is deemed to be highly infectious with an R0 rating of 12 to 18. The R0 rating stands for the reproduction number of the virus and the subsequent number of secondary infections that would occur if it was introduced to a susceptible population (Moss & Griffin, 2006). These secondary infections are the primary cause of mortality in those with an acute measles infection (Griffin, Lin, & Pan, 2012). The virus is primarily transmitted by a person carrying it in their respiratory tract who expels it in the form of large droplets by coughing (Laksono et al., 2016). The virus is then in the form of either cell-associated or cell-free virus particles which allow it to be taken into the respiratory tract of those exposed to it (Laksono et al., 2016). Once inside the respiratory tract, the virus performs a primary infection of the macrophages and dendric cells present in the lungs (Young & Rall, 2009), (Hussein, 2014). After this initial infection the virus then enters local lymphatic pathways which enables it to eventually be drained into a lymph node where it can begin replication eventually resulting in viremia (Yanagi, Takeda & Ohno, 2006). The virus is also capable (in rare cases) of infecting the central nervous system (CNS) (Young & Rall, 2009) possibly due to cell to cell spread in a spread non-cytolytic process (Plattet, Alves, Herren, & Aguilar, 2016).
Table 1: Measles genotypes associated with both endemic transmission and importation.
The UK has the B3, D4, D5, D8 and D9 measles genotype which are associated with importation from other countries which carry these genotypes (Rota et al., 2011).
The measles virus is only found in humans and has not been detected in any other species. It is capable of surviving outside of a human host for around 1 hour, with one of the primary factors affecting its survival being the relative humidity in the air. If the humidity is below 40% or above 80% the virus is in a stable condition (Laksono et al., 2016). According to the World Health Organization (WHO), there were over 89,780 children globally who died from the disease in 2016 (WHO, 2018).
The virus is an enveloped, non-segmented, negative-strand RNA virus. The envelope is made up of nucleocapsid (N) protein which forms a helical ribonucleoprotein (RNP) complex. This complex is coupled with a large (L) protein that functions as a viral RNA-dependent RNA polymerase as well as the phosphoprotein (P) which is a polymerase cofactor (Rota et al., 2016). There are also two glycoproteins on its envelope, which consist of a fusion protein (MV-F) and an attachment protein hemagglutinin (MV-H) (Hashiguchi, Maenaka, & Yanagi, 2011). The MV-H is responsible for the initial receptor binding in the host cell and forms a hetero-oligomer with the MV-F in order to mediate membrane fusion (Hashiguchi, Maenaka, & Yanagi, 2011).
The manner in which the virus is able to bind to the host cell and mediate membrane fusion begins with the signalling lymphocyte activation molecule (SLAM) which is present on both macrophages and dendric cells (Gonçalves-Carneiro, McKeating & Bailey, 2017). In particular, the SLAM present on these lymphocytes is also termed as CD150 and plays a vital role in the formation of immunological synapses, thymocyte maturation and lymphocyte development (Chan et al., 2003). The CD150 is the primary entry receptor in which the virus binds using its MV-H protein (Gonçalves-Carneiro, McKeating & Bailey, 2017). Once this binding has taken place, the MV-H is believed to undergo a distinct change in structure thereby causing an additional structural change in the MV-F. This change that occurs in the MV-F is responsible for the subsequent fusion of the viral envelope to the host cell membrane (Hashiguchi, Maenaka, & Yanagi, 2011) (see figure 1). After this membranal fusion, the virus is able to release its RNP complex into the host cells cytoplasm where it undergoes a process of transcription and replication through the use of the encapsidated viral RNA as a template of RNA replicase complex (Jiang, Qin, & Chen, 2016). After transcription of the RNP, the viral mRNa that has been synthesised is translated into viral proteins through the use of the hosts own translation procedures (Jiang, Qin, & Chen, 2016). After translation, the viral proteins containing the MV-H and MV-F proteins are packaged in the Golgi Apparatus and can then be expressed on the host cell surface (Rota et al., 2016). The viral proteins containing both the MV-H and MV-F proteins can also meet with replicated RNP and matrix protein at the edge of the host cell to begin a budding process (Rota et al., 2016).
The transportation of the RNP complex to the plasma membrane is controlled by the matrix protein, with the overall process being dependent on microtubules associated with Rab11A (which is a Ras-related protein) as well as actin filaments (Jiang, Qin, & Chen, 2016). The expressed MV-H and MV-F are capable of enabling cell to cell fusion with uninfected neighbouring cells to again, begin the process of viral reproduction (Tahara, Takeda, & Yanagi, 2007). This infection of immune cells enables the virus to eventually infect epithelial tissue in the respiratory tract via the migration of the immune cells through it. In order to effectively bind to the epithelial tissue, the virus uses a separate receptor called nectin-4 which is present on the tissue (Mühlebach et al., 2011). This will consequently lead to future transmission of the virus to new individuals (Gonçalves-Carneiro, McKeating & Bailey, 2017).
Figure 1: Structure of the measles virus and its process of infection.
a. The basic structure of the measles virus is displayed. Its components include a lipid bilayer, a matrix protein, a nucleocapsid protein, a haemagglutinin protein, a phosphoprotein, a large protein and a fusion protein (Rota et al., 2016). b. The process of the virus’s infection and subsequent replication within the host cell are displayed.
The innate immune response of the host that would usually activate immediately in the presence of an infection is restricted due to the inhibition of the interferon response (Griffin, 2016). During this time the virus is able to replicate and spread throughout the body but does not show symptoms for around 10 to 14 days. It is only once the presence of the maculopapular rash is identified that the host adaptive immune response has begun (Griffin, 2016). However, it’s absence could suggest diminished immune function and an increase in the severity of the infection (Permar et al., 2003).
The rash is indictive of the presence of the T cells CD4+ and CD8+ in epithelial cells where there is measles virus infection (Permar et al., 2003). These T cells are responsible for clearing the infectious virus (the viremia) by infiltrating sites of viral replication, with the process taking approximately 20 days after the start of infection. Surprisingly, the presence of measles viral RNA within the circulation of the host persists for up to 4 months (Griffin, Lin, & Pan, 2012). During the persistence of the viral RNA there is a change in the production of T cells with the T type 2 helper cell CD4+ being produced at a much higher rate. This production is believed to subsequently, result in the promotion of B-cell maturation as well as antibody responses (Griffin, 2016). This has however, been noted as a possible cause of suppression of macrophages as well as T type 1 helper cells and their responses to secondary infections (Griffin, 2016).
After having the measles virus, the hosts immune system has produced plasma cells which are long-lived and responsible for the production of plasma antibodies (Amanna & Slifka, 2010). These plasma antibodies are present in the host for life and are specifically designed to target the virus should it ever appear in the host again. T cell immunity has also been noted to be of importance as a protective factor against repeated measles infection for those who produce low levels of measles specific antibodies (Griffin, 2016). However, as the T cells are responsible for only eliminating infected cells once they are already present, they are not generally considered to be major protective elements and are not entirely capable of preventing further measles infection (Griffin, 2016).
Due to measles being a viral infection there are no prescription medications that can be given to cure the condition. It has been suggested that vitamin A treatment can be given in 2 dosages of differing amounts depending on the age of the person infected with the virus (Sudfeld, Navar, & Halsey, 2010). Vitamin A is responsible for maintaining respiratory as well as gastrointestinal epithelia. It is also involved in the regulation of immune functioning in humans with a deficiency of it being responsible for an increased susceptibility to infections (Imdad et al., 2011). The routine vitamin A treatment is believed to work by alleviating symptoms such as diarrhoea which is responsible for increasing mortality rates through dehydration (Sudfeld, Navar, & Halsey, 2010).
The primary method behind measles prevention is through the administration of a vaccine. The vaccine is made up of a live attenuated, wild type strain of the measles virus that has been treated in a way in which it loses its virulence factors without affecting its ability to induce immunity (Hussein, 2014). The vaccine is typically given in combination with mumps and rubella at an age of 18 months and again between the ages of 4 and 5 (Hussein, 2014). The reason the vaccine is not given earlier than 18 months is to avoid the interaction of the vaccine with measles virus antibodies from the mother, which are capable of preventing the vaccine from being effective (Hussein, 2014). The live attenuated feature of the vaccine enables it to perform an asymptomatic infection of the host whilst still allowing for induction of long-lasting immunity (Hussein, 2014).
With the measles vaccine only being given to children of around 18 months, the consensus appears to be that an infant would avoid exposure of this disease through herd immunity (see figure 2). Shockingly, despite the clear advantages of administration of the measles vaccine to the general populous, numbers of individuals receiving the vaccine in England was shown to decline after a report published in 1998 which made fraudulent claims on a link between the vaccine and autism. Autism is first detected in infants at around 18 months further enabling false correlations between it and administration of the measles vaccine (Ozonoff, Heung, Byrd, Hansen & Hertz-Picciotto, 2008). Numbers did rise again to around 91.6% in 2016-17 but have since declined further to 91.2% which is the lowest amount since 2011-12 (Wise, 2018). In order to counteract this decline, it is necessary to change public mindset by placating any worries present on the vaccination and to make information more easily available/accessible.
Figure 2: Herd immunity in populations
A. Potential pathogens are fully mobile between populations. B. Isolation by surrounding immune individuals prevents transmission to those susceptible (Fine, Eames & Heymann, 2011).
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