Pathogenesis of measles virus infection The WritePass Journal

Pathogenesis of measles virus infection Introduction Pathogenesis of measles virus infection IntroductionSymptomsVaccinationSubacute Sclerosing Panencephalitis  ConclusionRelated 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 cellul ar 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-ÃŽ ³ 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) wh ich 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 manife st 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. Pathogenesis of measles virus infection Introduction Pathogenesis of measles virus infection IntroductionInfection1. Attachment2. Fusion3. RNA replication and Assembly of viral particles4. Release of virusSpread1. Changes in lymphocyte number and function2. Shift in cytokine profile3. Impaired antigen presentationSymptomsImmunosuppressionVaccinationSubacute sclerosing panencephalitis (SSPE)BibliographyRelated Introduction Measles is a highly contagious disease caused by an enveloped RNA virus of the genus Morbillivirus in the family of Paramyxoviridae (Griffin et al, 1994). It is a major cause of child morbidity and mortality, particularly in developing countries, despite the introduction of attenuated measles virus vaccines which have greatly reduced the incidences since the 1960s (WHO, 2009). The window period of infection for infants lies between the disappearing maternal antibody protection and vaccine administration (Manchester and Rall, 2001). In 2008, 164,000 measles deaths were reported and majority was children under five years old (WHO, 2009). Affected individuals combat measles by generating cell mediated immunity to clear the virus and humoral immunity to provide long-term protection (Manchester and Rall, 2001). However, measles virus (MV) induces immunosuppression during infection and for weeks after recovery, rendering infected individuals susceptible to secondary infections (Griffin et al, 1994). The evidence of immunosuppression caused was first recognized in 1908 when von Pirquet reported that children lost positive skin test for tuberculin antigen during MV infection (von Pirquet, 1908). Research has been carried in vitro and in vivo in order to define the pathogenesis pathways of MV. Immune responses to MV have been described on transgenic mice and cynomolgus monkeys models (Sato et al, 2007) suggesting that multiple potential mechanisms are linked to the virus-induced immunosuppression (Schneider-Schaulies et al, 2002). Infection Measles is transmitted via airborne exposure from coughing and sneezing or close contact with nasal and throat secretions. MV remains active in the air for up to two hours. It enters the body through the respiratory system and spread systemically by infecting lymphoid cells. Infection and spread is a complex process. The structure and proteins of MV are important determinants of virus tropism and pathogenesis (Yanagi et al, 2006). Measles virus consists of a non-segmented single negative-strand RNA genome (16,000 ribonucleotides) with a diameter of 150 to 300 nm. The outer envelope comprises with the inner matrix protein to form a lipid bilayer surrounding the viral genome. It encodes six structural proteins and two nonstructural proteins which are important for attachment of the virus to the host, replication and spreading of the virus in the body (Horikami et al, 1995). Table 1 briefly describes the functions and locations of structural components and Figure 1 illustrates the structure of a measles virus. Table 1: Locations and functions of Measles virus structural proteins Structural proteins    Locations Functions 1. Haemagglutinin(H) Both H and F proteins are surface transmembrane glycoproteins. They project from the lipid bilayer and traverse the internal matrix. Responsible for the initiation of infection. H protein: receptor binding and cell fusion F protein: cell fusion and viral entry. 2. Fusion proteins (F) 3. Nucleoprotein (N) Surround the RNA strand Form a ribonucleocapsid. 4. Phosphoprotein (P) Both P and L proteins are associated with the ribonucleocapsid The ribonucleoprotein complex acts as RNA polymerase and is responsible for RNA replication and transcription. 5. Large polymerase protein (L) 6. Matrix protein (M) Attaches to the inner surface of the envelope Assembly of the viral particles. Virus budding. Adapted from (Yanagi et al, 2006) The nonstructural protein C and V are encoded on the P gene by RNA editing and alternative translation. Patterson et al (2000) showed that C and V proteins functioned as virulence factors in CNS measles infection using YAC-CD46 transgenic mice. In addition, C protein is capable to inhibit viral transcription and enhancing MV particles assembly. These proteins have shown to be involved in inhibition of interferon production (Naniche et al, 2000). The infection process involves four steps: 1. Attachment When measles virus enters the respiratory tract, the initial infection begins with viral attachment to host cellular receptors by the haemagglutinin (H) protein. The most studied receptors are CD46 and signaling lymphocytic activation molecule (SLAM/ CD150) (Ferreira et al, 2010). CD46 is a complement regulatory molecule and is present on all nucleated human cells whereas SLAM is only expressed on thymocytes, mature dendritic cells and T and B lymphocytes (Hsu et al, 2001). Other cell surface proteins such as moesin and substance P receptor were also proposed in MV binding (Kehren et al, 2001). The primary target for early stage infection has not been clearly defined. It was originally thought that respiratory epithelial cells were firstly infected (Griffin, 2001) but following the discovery of SLAM, some studies suggested that SLAM-positive immune cells should be the initial targets (Yanagi et al, 2002). Leonard et al. (2008) suggested the presence of a basolateral epithelial recept or (EpR) is necessary for entry of MV into respiratory epithelium and infection of the epithelial cells is required for shedding and transmission. Figure 1: a) Structure of a measles virus   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   b) Measles virus genome   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   c) Membrane fusion and replication of measles virus in a cell   Take from the wed-site nature.com/nrmicro/journal/v4/n12/box/nrmicro1550_BX1.html (Moss Griffin, 2006) 2. Fusion The interaction of both H and F proteins with human receptors is important for the virus to gain access into the host cell. Fusion (F) protein mediates the fusion of viral envelop with cell membrane. Figure 1 (c) demonstrated the fusion process. When the tetramer H protein binds to its receptor, it generates a conformational change within the F protein which is composed of two subunits F1 and F2 linked by a disulphide bond. The activated F protein inserts the hydrophobic fusion peptide into the target cell membrane and provides entry of the viral genome into the host cell interior (Weidmann et al, 1999). 3. RNA replication and Assembly of viral particles The polymerase allows replication and transcription of the genome within the cell. The negative sense RNA is copied into a complementary positive strand which, in turn, acts as a template for the negative strand. Viral components are translated in the cell and are assembled at the cell surface (Yanagi et al, 2006). 4. Release of virus MV leaves the host cell in a budding form (Yanagi et al, 2006). Spread The viremic spread from the respiratory tract is carried out by infected immune cells including monocytes, dendritic cells, B and T cells which travel through the local lymphatics and are transported to the secondary lymphoid tissue where further viral replication occurs. A secondary viremia occurs when infected cells enter the circulation and viral replication continues in the endothelia and epithelia of other organs including skin, gastrointestinal tract, liver, kidney and central nervous system (Ferreira et al, 2010). A systemic spread is favored by the immunosuppression following infection. Multiple mechanisms are involved in the development of immunosuppression and a brief description below focuses on some of the important pathways. 1. Changes in lymphocyte number and function Lymphopenia of B and T cells during viremic and post-clinical recovery stages is demonstrated by many studies. Bieback et al. (2002) showed that MV can bind to Toll-like receptor (TLR) 2 on monocytes, inducing SLAM expression and interleukin-6 (IL-6) production. In addition, binding of SLAM can induce Fas (CD95)-mediated apoptosis of uninfected CD4+ and CD8+ T lymphocytes. The extracellular composition of CD46 is characterized by four short consensus repeat (SCR) and a STP domain. SCRs 2, 3 and 4 are binding regions for C3b and C4b, thereby preventing them from causing autologous complement lysis. The attachment of MV to SCRs 1 and 2 alters the normal signaling pathway resulting in down-regulation of CD46, eventually leading to increased C3b-mediated complement lysis (Manchester and Rall, 2001). MV also inhibits lymphoproliferation by causing cell cycle arrest in the G0/G1 phase in dividing lymphocytes (Niewiesk et al, 1999) and interferes with NF-kB signaling pathways and anti-apoptotic B cell lymphoma 3 (Bcl-3) proteins (Bolt Berg, 2002). Furthermore, Nucleoprotein of MV binds to the Fc-gamma receptor on antigen presenting cells and impairs their ability to stimulate T cell proliferation (Hehren et al, 2001). Figure 2 summarized the main pathways leading to immunosuppression. Figure 2: Mechanisms of immunosuppression following measles virus infection Adapted from (Moss et al, 2004) 2. Shift in cytokine profile Early evasion of the innate immune responses is the interference of interferon-alpha/beta signaling pathways (Naniche et al, 2000) due to inhibition of STAT1 and STAT2 phosphorylation by proteins V and C. However, IFN-gamma production is not affected in the acute phase of measles (Takeuchi et al, 2003). Cross-linking of CD46 by MV and direct binding of MV to CD46 on monocytes and dendritic cells inhibit the production of IL-12 (Karp et al, 1996) and hence suppress macrophage activation, T cell proliferation and delayed-type hypersensitivity (Atabani et al, 2001). The loss of IL-12 also decreases type 1 cytokines TNF-alpha and IL-2, leading to transition to type 2 cytokines IL-4, IL-5 and IL-10 by CD4+ T cells (Moss et al, 2002). Th1 to Th2 shift leads to a change of cell-mediated immunity to a dominant humoral immunity which is not sufficient to combat new infections (Kemper et al, 2003). 3. Impaired antigen presentation Dendritic cells are critical for the antigen presentation to naà ¯ve T lymphocyte. MV infected dendritic cells fail to undergo differentiation to become mature effector cells and some of them are susceptible to Fas-mediated apoptosis (Servet-Delprat et al, 2000). Marttila et al (2001) reported that antigen processing of other viruses such as rubella virus and coxsackie B4 virus is compromised in MV-infected human mononuclear cells, suggesting impaired antigen presentation to T cells. Symptoms The clinical presentation is induced by the immune responses. The initial encounter of the virus activates the innate immunity with high levels of IFN-ÃŽ ³ and IL-8 but it is not efficient to clear the virus, leading to rapid multiplication of virus (Sato et al, 2008). Figure 3 illustrates the timeline of viremia and appearance of symptoms. Figure 3: Pathogenesis of measles virus and immune responses of host. Obtained from http://pathmicro.med.sc.edu/mhunt/mump-meas.htm (Hunt, 2008) The early symptoms of measles, listed below, usually appear after an incubation period of 10 to 12 days and last for 2 to 4 days due to inflammatory reactions affecting the respiratory tract and conjunctiva (Griffin, 1995). Fever Malaise Coryza Cough Small white spots in the oral cavity (Koplik’s spots) Conjunctivitis Rash The appearance of maculopapular rash reflects the immune complex formation in the skin. It correlates with viremia and onset of adaptive immune responses. The rash starts on the face and upper back after 14 days of exposure and spreads to the entire body over the next 3 days and finally fades after 5 to 6 days indicating that Cytotoxic T lymphocytes destroy infected host cells and clear the virus. Measles antibodies also appear in the circulation around this time with IgM at day 10 and IgG at day 14. They reduce measles viral load through serum neutralization. IFN-ÃŽ ³ and IL-8 levels decrease at convalescent as cytotoxic T cells decline (Heffernan and Keeling, 2008). Immunosuppression The most important pathologic feature of measles virus is immunosuppression. Most measles-related deaths are caused by secondary bacterial and viral infections. Malnourished children with weakened immune system and vitamin A deficiency are at high risk of developing complications which include blindness, diarrhoea, bronchitis, encephalitis, ear infection and pneumonia. Patients with impaired cell-mediated immunity may not develop the rash and they are susceptible to giant cell pneumonia (Manchester and Rall, 2001) Vaccination There is no antiviral therapy for measles although medications can reduce complications. Vaccination is currently the best method to prevent the disease. The first MV called Edmonston strain was isolated in 1954 on primary human kidney cells and it was subsequently adapted to chicken embryo fibroblasts and become the progenitor for currently used attenuated live vaccines. Composition of vaccines is important to elicit long-term protective immunity but not immunologic reactions and clinically significant immunosuppression. Measles vaccine is now usually given as part of a trivalent combined vaccine, MMR which is also against mumps and rubella (Hilleman, 1999). The World Health Organization has recommended infants should have the first administration of measles vaccine at 9 to 12 months because immunity requires Th1-type response. For countries with high measles transmission, a second dose should be given at age 15 to 18 months (WHO, 2009). Vaccination campaigns are effective in promoting the use of vaccination and reducing measles deaths. Between 2002 and 2008, measles vaccination has significantly reduced 78% of measles deaths from an estimated 733 000 in 2000 to 164 000 in 2008. However, many developing countries, particularly parts of Africa and Asia, still suffer from this preventable infection due to the poor access to vaccinations and lack of facilities to properly store vaccines (Manchester and Rall, 2001). Ohtake et al (2010) has reported a spray drying method was successful to produce heat-stable measles vaccine powders. However, further tests are required to demonstrate the feasibility of these dry vaccines. Molecular epidemiology is a useful tool to monitor measles and genomic study of measles virus can provide insight in the development of new and safe vaccines (Ohtake et al, 2010). The World Health Organization is making an effort to monitor outbreaks and increase immunization coverage and hopefully can ev entually eradicate the virus in the future. Subacute sclerosing panencephalitis (SSPE) SSPE is a fatal disease caused by a persistent infection with a defected form of measles virus in the brain. The common mutated components are the matrix (M), the fusion (F) and the haemagglutinin (H) proteins. Mutations can be point mutations, deletions and biased hypermutations and are mostly found in the M gene (Gutierrez et al, 2010). SSPE has a slow progression and usually develops in an interval of 5 to 10 years after the initial infection. It is very rare. Incidence rate varies between countries but the average is about one per million. Age and sex of infected individuals can affect the frequency of SSPE. Infection before the age of 2 years is associated with higher occurrences and boys are 2 times more likely to acquire SSPE (Gutierrez et al, 2010). The development of SSPE is caused by an imcompleted eradication of MV due to inadequate cell-mediated responses caused by genetic polymorphisms (Yentur et al, 2005) and high level of IL-4 but low levels of IL-12. These cytokines favour humoral response and predispose to viral replication (Hara et al, 2006). MV enters neurons by binding to host receptors CD46 and CD9 using the F protein. It replicates inside the cells and spreads to neighbouring neurons by neurokinins synaptic receptors (Makhortova et al, 2007). In addition, sequence analysis of viral RNA showed that the virus was entered from one point and disseminate throughout the brain. The defective structural envelope proteins assist them to escape from the immune system as the mutated M, F and H proteins failed to assemble and bud out the cells. Thus, the viral particles are not recognized for many years. However, inflammatory responses are finally triggered when the virus damages the host DNA and induces apoptosis (Oldstone et al, 2004). Histological examination of the brain tissue shows evidence of widespread demyelination, infiltration of immune cells and blood brain barrier damage. Glia cells and astrocytes may be activated with increased expression of MHC class II molecules and tumor necrosis factor-ÃŽ ±. Appearance of inclusion bodies in brain tissue is also common (Akram et al, 2008). Patients are often diagnosed based on presentation and clinical findings of electroencephalography, magnetic resonance imaging and CSF serology (Koppel et al, 1996). 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