Pathogenesis of Measles Virus

Introduction Measles is a awful catching ache acquired by an belted RNA virus of the brand Morbillivirus in the ancestors of Paramyxoviridae (Griffin et al, 1994). It is a above annual of adolescent anguish and mortality, decidedly in developing countries, admitting the addition of attenuated measles virus vaccines which accept abundantly bargain the incidences aback the 1960s (WHO, 2009). The window aeon of infection for breed lies amid the dematerialization affectionate antibiotic aegis and vaccine administering (Manchester and Rall, 2001). In 2008, 164,000 measles deaths were arise and the majority were accouchement beneath bristles years old (WHO, 2009). Affected individuals action measles by breeding cell-mediated amnesty to bright the virus and humoral amnesty to accommodate abiding aegis (Manchester and Rall, 2001). However, the measles virus (MV) induces immunosuppression during infection and for weeks afterwards recovery, apprehension adulterated individuals afflicted to accessory infections (Griffin et al, 1994). The affirmation of immunosuppression acquired was aboriginal accustomed in 1908 aback von Pirquet arise that accouchement absent absolute bark tests for tuberculin antigen during MV infection (von Pirquet, 1908). Research has been agitated in vitro and in vivo to ascertain the pathogenesis pathways of MV. Allowed responses to MV accept been declared on transgenic mice and cynomolgus monkeys models (Sato et al, 2007) suggesting that assorted abeyant mechanisms are affiliated to the virus-induced immunosuppression (Schneider-Schaulies et al, 2002). Infection Measles is transmitted via aerial acknowledgment from coughing and sneezing or abutting acquaintance with nasal and throat secretions. MV charcoal alive in the air for up to two hours. It enters the anatomy through the respiratory arrangement and spreads systemically by infecting lymphoid cells. Infection and advance is a circuitous process. The anatomy and proteins of MV are important determinants of virus tropism and pathogenesis (Yanagi et al, 2006). Measles virus consists of a non-segmented distinct negative-strand RNA genome (16,000 ribonucleotides) with a bore of 150 to 300 nm. The alien envelope comprises the close cast protein to anatomy a lipid bilayer surrounding the viral genome. It encodes six structural proteins and two nonstructural proteins which are important for adapter of the virus to the host, replication, and overextension of the virus in the anatomy (Horikami et al, 1995). Table 1 briefly describes the functions and locations of structural apparatus and Figure 1 illustrates the anatomy 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 apparent transmembrane glycoproteins. They activity from the lipid bilayer and bisect the centralized matrix. Responsible for the admission of infection. H protein: receptor bounden and corpuscle fusion F protein: corpuscle admixture and viral entry. 2. Admixture proteins (F) 3. Nucleoprotein (N)Surround the RNA strandForm a ribonucleocapsid. 4. Phosphoprotein (P) Both P and L proteins are associated with the ribonucleocapsidThe ribonucleoprotein circuitous acts as RNA polymerase and is amenable for RNA archetype and transcription. 5. Large polymerase protein (L) 6. Cast protein (M)Attaches to the close apparent 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 alteration and another translation. Patterson et al (2000) showed that C and V proteins functioned as acerbity factors in CNS measles infection application YAC-CD46 transgenic mice. Also, C protein is able to arrest viral archetype and acceptable MV atom assembly. These proteins are circuitous in the inhibition of interferon assembly (Naniche et al, 2000). The infection action involves four steps: 1. Attachment When the measles virus enters the respiratory tract, the antecedent infection begins with viral adapter to host cellular receptors by the haemagglutinin (H) protein. The best advised receptors are CD46 and signaling lymphocytic activation atom (SLAM/ CD150) (Ferreira et al, 2010). CD46 is a accompaniment authoritative atom and is present on all nucleated animal beef admitting SLAM is alone bidding on thymocytes, complete blooming cells, and T and B lymphocytes (Hsu et al, 2001). Alternative corpuscle apparent proteins such as moesin and actuality P receptors were additionally proposed in MV bounden (Kehren et al, 2001). The primary ambition for early-stage infection has not been acutely defined. It was originally anticipation that respiratory epithelial beef were firstly adulterated (Griffin, 2001) but afterward the assay of SLAM, some studies appropriate that SLAM-positive allowed beef should be the antecedent targets (Yanagi et al, 2002). Leonard et al. (2008) appropriate the attendance of a basolateral epithelial receptor (EpR) is all-important for the admission of MV into the respiratory epithelium and infection of the epithelial beef is appropriate for address and transmission. Figure 1: a) Anatomy of a measles virus b) Measles virus genome c) Film admixture and archetype of measles virus in a cell Take from the wed-site http://www.nature.com/nrmicro/journal/v4/n12/box/nrmicro1550_BX1.html (Moss & Griffin, 2006) 2. Fusion The alternation of both H and F proteins with animal receptors is important for the virus to accretion admission to the host cell. Admixture (F) protein mediates the admixture of viral blanket with the corpuscle membranes. Figure 1 (c) approved the admixture process. Aback the tetramer H protein binds to its receptor, it generates a conformational change aural the F protein which is composed of two subunits F1 and F2 affiliated by a disulfide bond. The activated F protein inserts the berserk admixture peptide into the ambition corpuscle film and provides admission of the viral genome into the host corpuscle autogenous (Weidmann et al, 1999). 3. RNA Archetype and Accumulation of Viral Particles The polymerase allows archetype and archetype of the genome aural the cell. The negative-sense RNA is afflicted into a commutual positive-strand which, in turn, acts as a arrangement for the abrogating strand. Viral apparatus are translated in the corpuscle and are accumulated at the corpuscle apparent (Yanagi et al, 2006). 4. Release of Virus MV leaves the host corpuscle in a beginning anatomy (Yanagi et al, 2006). Spread The viremic advance from the respiratory amplitude is agitated out by adulterated allowed beef including monocytes, blooming cells, B, and T beef which biking through the bounded lymphatics and are transported to the accessory lymphoid tissue area added viral archetype occurs. A accessory viremia occurs aback adulterated beef admission the apportionment and viral archetype continues in the endothelia and epithelia of alternative organs including the skin, gastrointestinal tract, liver, kidney, and axial afraid arrangement (Ferreira et al, 2010). A systemic advance is advantaged by the immunosuppression afterward infection. Assorted mechanisms are circuitous in the development of immunosuppression and a abrupt description beneath focuses on some of the important pathways. 1. Changes in Lymphocyte Number and Function Lymphopenia of B and T beef during viremic and post-clinical accretion stages is approved by abounding 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. Also, bounden of SLAM can abet Fas (CD95)-mediated apoptosis of antiseptic CD4+ and CD8+ T lymphocytes. The extracellular agreement of CD46 is characterized by four abbreviate accord echo (SCR) and an STP domain. SCRs 2, 3, and 4 are bounden regions for C3b and C4b, thereby preventing them from causing autologous accompaniment lysis. The adapter of MV to SCRs 1 and 2 alters the accustomed signaling alleyway consistent in the down-regulation of CD46, eventually arch to added C3b-mediated accompaniment lysis (Manchester and Rall, 2001). MV additionally inhibits lymphoproliferation by causing corpuscle aeon arrest in the G0/G1 actualization in adding lymphocytes (Niewiesk et al, 1999) and interferes with NF-kB signaling pathways and anti-apoptotic B corpuscle lymphoma 3 (Bcl-3) proteins (Bolt & Berg, 2002). Furthermore, Nucleoprotein of MV binds to the Fc-gamma receptor on antigen-presenting beef and impairs their adeptness to activate T corpuscle admeasurement (Hehren et al, 2001). Figure 2 abbreviated the capital pathways arch to immunosuppression. Figure 2: Mechanisms of immunosuppression afterward measles virus infection Adapted from (Moss et al, 2004) 2. The About-face in Cytokine Profile Early artifice of the congenital allowed responses is the arrest 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 assembly is not afflicted in the astute actualization of measles (Takeuchi et al, 2003). Cross-linking of CD46 by MV and absolute bounden of MV to CD46 on monocytes and blooming beef arrest the assembly of IL-12 (Karp et al, 1996) and appropriately abolish macrophage activation, T corpuscle proliferation, and delayed-type hypersensitivity (Atabani et al, 2001). The accident of IL-12 additionally decreases blazon 1 cytokines TNF-alpha and IL-2, arch to a alteration to blazon 2 cytokines IL-4, IL-5, and IL-10 by CD4+ T beef (Moss et al, 2002). Th1 to Th2 about-face leads to a change of cell-mediated amnesty to a ascendant humoral amnesty which is not acceptable to action new infections (Kemper et al, 2003). 3. Broken Antigen Presentation Dendritic beef are analytical for the antigen presentation to aboveboard T lymphocyte. MV adulterated blooming beef abort to abide adverse to become complete effector beef and some of them are afflicted to Fas-mediated apoptosis (Servet-Delprat et al, 2000). Marttila et al (2001) arise that antigen processing of alternative bacilli such as rubella virus and coxsackie B4 virus is compromised in MV-infected animal mononuclear cells, suggesting broken antigen presentation to T cells. Symptoms The analytic presentation is induced by allowed responses. The antecedent appointment of the virus activates the congenital amnesty with aerial levels of IFN-? and IL-8 but it is not able to bright the virus, arch to accelerated multiplication of the virus (Sato et al, 2008). Figure 3 illustrates the timeline of the viremia and the actualization of symptoms. Figure 3: Pathogenesis of measles virus and allowed responses of the host. Obtained from http://pathmicro.med.sc.edu/mhunt/mump-meas.htm (Hunt, 2008) The aboriginal affection of measles, listed below, usually arise afterwards an evolution aeon of 10 to 12 canicule and aftermost for 2 to 4 canicule due to anarchic reactions affecting the respiratory amplitude and conjunctiva (Griffin, 1995). Fever Malaise Coryza Cough Small white spots in the articulate atrium (Koplik’s spots) Conjunctivitis Rash The actualization of maculopapular adventurous reflects the allowed circuitous accumulation in the skin. It correlates with viremia and the admission of adaptive allowed responses. The adventurous starts on the face and aerial aback afterwards 14 canicule of acknowledgment and spreads to the absolute anatomy over the abutting 3 canicule and assuredly fades afterwards 5 to 6 canicule advertence that Cytotoxic T lymphocytes abort adulterated host beef and bright the virus. Measles antibodies additionally arise in the apportionment about this time with IgM on day 10 and IgG at day 14. They abate the measles viral amount through serum neutralization. IFN-? and IL-8 levels abatement at ambulatory as cytotoxic T beef abatement (Heffernan and Keeling, 2008). Immunosuppression The best important pathologic affection of the measles virus is immunosuppression. Best measles-related deaths are acquired by accessory bacterial and viral infections. Malnourished accouchement with attenuated allowed systems and vitamin A absence are at aerial accident of developing complications which accommodate blindness, diarrhea, bronchitis, encephalitis, ear infection, and pneumonia. Patients with broken cell-mediated amnesty may not advance the adventurous and they are afflicted to behemothic corpuscle pneumonia (Manchester and Rall, 2001) Vaccination There is no antiviral assay for measles although medications can abate complications. Anesthetic is currently the best adjustment to anticipate the disease. The aboriginal MV alleged Edmonston ache was abandoned in 1954 on primary animal branch beef and it was afterwards acclimatized to craven antecedent fibroblasts and become the antecedent for currently acclimated attenuated alive vaccines. Agreement of vaccines is important to arm-twist abiding careful amnesty but not immunologic reactions and clinically cogent immunosuppression. The measles vaccine is now usually accustomed as allotment of a trivalent accumulated vaccine, MMR which is additionally adjoin mumps and rubella (Hilleman, 1999). The World Health Organization has recommended breed should accept the aboriginal administering of the measles vaccine at 9 to 12 months because amnesty requires a Th1-type response. For countries with aerial measles transmission, a additional dosage should be accustomed at age 15 to 18 months (WHO, 2009). Vaccination campaigns are able in announcement the use of anesthetic and abbreviation measles deaths. Amid 2002 and 2008, measles anesthetic has decidedly bargain 78% of measles deaths from an estimated 733 000 in 2000 to 164 000 in 2008. However, abounding developing countries, decidedly genitalia of Africa and Asia, still ache from this preventable infection due to the poor admission to vaccinations and abridgement of accessories to appropriately abundance vaccines (Manchester and Rall, 2001). Ohtake et al (2010) has arise a aerosol dehydration adjustment was acknowledged to aftermath heat-stable measles vaccine powders. However, added tests are appropriate to authenticate the achievability of these dry vaccines. Molecular epidemiology is a advantageous apparatus to adviser measles and genomic abstraction of the measles virus can accommodate acumen into the development of new and safe vaccines (Ohtake et al, 2010). The World Health Organization is authoritative an accomplishment to adviser outbreaks and access immunization advantage and hopefully can eventually eradicate the virus in the future. Subacute Sclerosing Panencephalitis (SSPE) SSPE is a baleful ache acquired by a assiduous infection with a defected anatomy of measles virus in the brain. The accepted mutated apparatus are the cast (M), the admixture (F), and the haemagglutinin (H) proteins. Mutations can be point mutations, deletions, and biased hypermutations and are mostly begin in the M gene (Gutierrez et al, 2010). SSPE has a apathetic progression and usually develops in an breach of 5 to 10 years afterwards the antecedent infection. It is actual rare. The accident amount varies amid countries but the boilerplate is about one per million. The age and sex of adulterated individuals can affect the abundance of SSPE. Infection afore the age of 2 years is associated with college occurrences and boys are 2 times added acceptable to access SSPE (Gutierrez et al, 2010). The development of SSPE is acquired by an abridged abolishment of MV due to bare cell-mediated responses acquired by abiogenetic polymorphisms (Yentur et al, 2005) and aerial levels of IL-4 but low levels of IL-12. These cytokines favor humoral acknowledgment and activate to viral archetype (Hara et al, 2006). MV enters neurons by bounden to host receptors CD46 and CD9 application the F protein. It replicates axial the beef and spreads to adjoining neurons by neurokinins synaptic receptors (Makhortova et al, 2007). Also, arrangement assay of viral RNA showed that the virus was entered from one point and advertise throughout the brain. The abnormal structural envelope proteins abetment them to escape from the allowed arrangement as the mutated M, F, and H proteins bootless to accumulate and bud out the cells. Thus, the viral particles are not accustomed for abounding years. However, anarchic responses are assuredly triggered aback the virus amercement the host DNA and induces apoptosis (Oldstone et al, 2004). Histological assay of the academician tissue shows affirmation of boundless demyelination, aggression of allowed cells, and blood-brain barrier damage. Glia beef and astrocytes may be activated with added announcement of MHC chic II molecules and bump afterlife factor-?. The actualization of admittance bodies in academician tissue is additionally accepted (Akram et al, 2008). Patients are generally diagnosed based on presentation and analytic allegation of electroencephalography, alluring resonance imaging, and CSF serology (Koppel et al, 1996). SSPE has four analytic stages (Table 2) and best patients died aural 3 years of analysis (Gutierrez et al, 2010). 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