Magoosh GRE

Pathogenesis of measles virus infection

| December 4, 2012

Introduction

Often dismissed in the developed world as a common childhood infection, measles are in fact a worrying contributor to childhood morbidity and mortality worldwide. In the UK alone, approximately 10% of cases result in complications requiring hospitalisation, 1 in 5,000 could be fatal [1]. This is much higher for the developing world where infection spreads rapidly in children that are living in close quarters, are malnourished and unable to avail of the vaccine.

In 1994, under the national schools vaccination campaign all school children aged 5-16 were offered the mumps-measles-rubella (MMR) vaccine. An uptake of 92% under this campaign resulted in measles being all but eradicated from England and Wales [2]. Unfortunately a fall in immunisation uptake over the last decade, amid fears of a link between MMR vaccine and autism, now means that the number of susceptible children is such that measles are once again endemic in the UK [3]. Epidemics are prevalent throughout European countries including Italy, Austria & Switzerland. Controlling a measles epidemic can be difficult, despite the availability of a safe and effective vaccine, as it is a highly infectious disease that spreads rapidly between susceptible individuals.

Infection & Spread

The measles virus (MV) is single stranded RNA Morbillivirus from the paramyxovirus family that results in an acute infection of respiratory and lymphoid tissues. It is a highly contagious disease transmissible via respiratory droplets that can remain viral on surfaces for up to two hours [1]. Although it’s spread via the respiratory route and symptoms are well established little is actually known of the cellular events underlying the disease.

Figure 1: Schematic diagram of measles structure [4]

To better understand the process of infection and spread we must take a closer look at the measles virus (MV). MV is single negative-strand enveloped RNA Morbillivirus that contains 15,894 base pairs encoding 8 proteins. As shown in figure 1 hemagglutinin (H) and fusion (F) proteins are transmembrane envelope proteins and as such their primary role is to initiate infection. Antibodies to these proteins may render the virus inactive [4].  The RNA genome is encapsidated by the nucleotide (N) protein forming a ribonucleocapsid complex which acts as the substrate for transcription and regulation [5]. The large protein (L) and phosphoprotein (P) are also associated with the ribonucleocapsid complex and hence replication and transcription.  The matrix protein (M) links the ribonucleocapsid complex to the envelope proteins during virus assembly [6]. There are also two non-structural proteins, C & V encoded within the P gene that act as regulators of infection by interacting with cellular proteins.

As previously mentioned binding of H to susceptible cells is an important instigating step in measles pathogenesis. Three viral receptors for H are identifiable, CD46 a low affinity protein present on all nucleated cells, an undetermined receptor on epithelial cells and SLAM / CD150, a high affinity receptor present on subsets of lymphocytes, thymocytes, macrophages and mature dendritic cells (DCs). SLAM/CD150 is the preferential receptor for wild type strains of MV.

Initially it was thought that MV infected respiratory epithelial cells which would in turn infect monocytes resulting in spread of infection to lymphoid tissues. However, this has been found not to be the case as monocytes only express CD46 low affinity receptors. Since then it has been demonstrated in vivo that lymphocytes expressing CD150 recpetors are the primary infected cells during measles in macaques [7]. However lymphocytes are not commonly found at respiratory epithelial cell surfaces hence MV target cells at transmission and throughout pathogenesis of MV are unclear.

It is thought that professional antigen presenting cells (APCs) known as dendritic cells may have a dual role in mediating transmission of the measles virus [8]. Although the expected role of DCs is to capture and present MV antigens for degradation, some escape degradation and are actually protected by DCs for transportation to lymphoid tissues. Here they encounter and infect CD150+ lymphocytes allowing replication of the virus.

From the primary lymphoid tissue, infected cells enter circulation. Infected peripheral blood mononuclear cells (PBMCs) are evident in the blood 7-9 days after infection [9].  From here the infection spreads to distal lymphoid tissues and to the epithelial and endothelial cells of multiple organs. Less is known about receptors used to infect these cells. There is however a number of cell surface molecules that interact with MV and as such may play an important role in MV pathogenesis, including receptor clustering, fusion, entry, cell-to-cell spread or cytokine production.  These include DC-SIGN, Toll like receptor 2 (TRL2), neurokinin-1 and Fc-γ receptor II. DC-SIGN (C-type lectin dendritic cell-specific ICAM-3 grabbing non-integrin) for example is credited with binding of MV to DCs. The role of which has been previously described for HIV1 [10] and has been demonstrated in MV infected macaques [7].  TRL2 interacts with H envelope protein to induce interleukin-6 (IL-6) which in turn stimulates the expression of CD150. TLR2 interaction with CD46 also inhibits IL-12 production.

Symptoms

Measles typically have an incubation period of 7-14 days. During the prodrome period of day 4-7 characteristic clinical symptoms of measles appear which include fever (often >104°F), cough, conjunctivitis and photophobia. Koplik spots, which are white buccal opposite the first and second upper molars, appear 2-3 days later followed by the maculopapular rash that lasts on average of 3-5 days [11] The rash is a manifestation of the adaptive immune response, and marks the start of viral clearance. Activated T cells and MV specific antibodies are present in circulation at this time and CD4+ and CD8+ cells have infiltrated sites of virus replication. Immunocompetent individuals will be successful in clearing the virus from these sites of replication and confer life long immunity to re-infection.

Interestingly, MV appears to have a contradictory effect on the immune system with acute infections predominantly linked to periods of transient immunosuppression, often lasting weeks after the disappearance of characteristic symptoms [8]. It is these periods of immunosuppression that leaves an individual susceptible to many associated secondary complications and ultimately MV related deaths. The risk of complications may increase in densely populated areas, in children infected under the age of two, pregnant women, malnourished individuals particularly those lacking in vitamin A and in individuals who have existing immunodeficiency. Complications include respiratory complications such as bronchopneumonia and giant cell pneumonitis, neurological complications such as acute demyelinating encephalitis, subacute sclerosing panencephalitis and measles inclusion body encephalitis, gastrointestinal complications like diarrhoea or clinical hepatitis and vitamin A deficiency which may manifest as xerophthalmia a leading cause of blindness worldwide [1].

The mechanisms that result in immunosuppression are not clearly understood but a number of methods are hypothesised. For example, there is noted decrease in the numbers of T cells and B cells during the rash which for the most part is attributed to an increase in CD95 mediated and lymphocyte apoptosis [9]. This may contribute to lymphopenia, however lymphocyte numbers generally return to normal as the rash clears. It is also thought that suppression of lymphocyte proliferation may be associated with G1 arrest of the cell cycle after infection with MV [12].  Similarly T-cell proliferation may be suppressed as a result of direct inhibitory signalling by the H and F1-F2 membrane viral complex which when in contact with a cell will delay S phase entry of T cells by several days leading to accumulation of cells in the G0-G1 cell cycle phase [9].

Yet another mechanism of immune suppression is type 2 skewing of CD4+ T-cells. During infection of APCs with MV there is marked decrease in production of IL-12, which plays an important role in T-cell production of type 1 cytokines [12]. Altered CD4+T production leads T cells that fail to proliferate.

Immunosuppression is characterised by lymphopenia, defective response to new antigens and a loss in the delayed type hypersensitivity responses to recall antigens.

Vaccination

A combined live attenuated mumps, measles and rubella (MMR) vaccine is the vaccine of choice against measles in more the 90 different countries worldwide. [13] Since its introduction in the 1970s the MMR vaccine has proven its capability to eliminate its target diseases from a number of countries. Following a national vaccination programme it was reported in 1996 that measles had all but been eradicated from the UK [2]. The US had similar success prior to this in 1993 [13] as did many other countries.

Numerous strains of the MMR vaccine are produced worldwide, many of which are derived from the Edmonston strain [14]. Four non Edmonston strains including Leningrad 16, Shanghai-191, CAM-70 and TD-97 are also in use [13]. The virus is generally cultured in chick embryo cells. Most vaccines also include a small dose of antibiotic. A number of combinations of these virus, mumps virus and rubella virus are used to produce a commercial MMR vaccine. There are five commonly used MMR vaccines on the market today including M-M-R by Merck, Morupar by Chiran, Priorix by Glaxo-Smith Klein, Trimovax by Pasteur Merieux Serums and Triviraten Berna.

Current US guidelines regarding vaccination with MMR recommend first dose at 12 months and a second dose to be administered before the age of 4, leaving at least 28 days between doses [15]. One dose and two dose vaccination strategies have been tried and tested in many countries [16, 17]. Although one dose strategies may achieve as much as 85% efficacy a second dose is essential to achieve eradication.

Unfortunately erroneous claims linking the MMR vaccine to autism and Crohn’s disease have led to a decline in uptake of MMR vaccine and as a result countries like the US, Germany, Austria and Italy are once again facing a measles epidemic [18].

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is an incurable complication of measles virus that presents itself 1-15years following acute MV infection [1]. It is most common in boys who under the age of two become infected with MV and is a far less common when MV infection occurs in adulthood [12]. SSPE occurs at the rate of 10,000-300,000 in acute MV infections. A disease affecting the central nervous system (CNS), SSPE initially presents as subtle cognitive changes, progressing to overt cognitive dysfunction, motor dysfunction, seizures, organ failure and eventual death. Neurons are initially targeted but as the disease progresses infected oligodendrocytes, astrocytes and endothelial cells have also been noted. Histologically it is characterised by cellular inclusion bodies, loss of neurons, inflammation, glial activation and deterioration of the blood brain barrier [12]. High numbers of MV specific antibodies are found in both blood and cerebrospinal fluid of SSPE patients.

 Conclusion

Little is actually known of how MV may cause SSPE and other associated MV complications. Early studies using brain biopsies of SSPE patients did however show that infected neurons were unable to release budding virus. Since then extensive sequencing of such cells have lead to the conclusion that point mutations of envelope associated genes, namely as H, M, and F, could result in defective protein expression and therefore do not allow infected neurons to complete the viral process [19]. How this impacts on the development of SSPE is unclear.

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