Orthomyxoviridae (2)

Editor's Notes

1. I had a little bird , its name was enza , I opened the window and influenza
2. The M1, M2, and NP proteins are type specific and are therefore used to differentiate influenza A from B or C viruses.
3. Mutation-derived changes in HA are responsible for the minor ("drift") and major ("shift") changes in antigenicity. Shifts occur only with influenza A virus, and the different HAs are designated H1, H2…H16. Mutation-derived changes in HA are responsible for the changes in antigenicity (shifts)
4. All the proteins are encoded on separate segments, with the exception of the nonstructural proteins (NS1 and NS2) and the M1 and M2 proteins, which are transcribed from one segment each.\ The HA has several functions. It is the viral attachment protein, binding to sialic acid on epithelial cell surface receptors; it promotes fusion of the envelope to the cell membrane at acidic pH; it hemagglutinates (binds and aggregates) human, chicken, and guinea pig red blood cells; and it elicits the protective neutralizing antibody response. Viral replication begins with the binding of HA to sialic acid on cell surface glycoproteins (Figure 57-2). The different HAs (HA1-16) bind to different sialic acid structures. The virus is then internalized into a coated vesicle and transferred to an endosome. Acidification of the endosome causes the HA to bend over and expose hydrophobic fusion-promoting regions of the protein. The viral envelope then fuses with the endosome membrane. The proton channel formed by the M2 protein promotes acidification of the envelope contents to break the interaction between the M1 protein and the NP, allowing uncoating and delivery of the nucleocapsid into the cytoplasm. Unlike most RNA viruses, the influenza nucleocapsid travels to the nucleus, where it is transcribed into messenger RNA (mRNA). The transcriptase (PA, PB1, and PB2) uses host cell mRNA as a primer for viral mRNA synthesis. In so doing, it steals the methylated cap region of the RNA, the sequence required for efficient binding to ribosomes. All the genomic segments are transcribed into 5'-capped, 3'-polyadenylated (polyA) mRNA for individual proteins except the segments for the M1, M2 and NS1, NS2 proteins, which are each differentially spliced (using cellular enzymes) to produce two different mRNAs The mRNAs are translated into protein in the cytoplasm. The HA and NA glycoproteins are processed by the endoplasmic reticulum and Golgi apparatus. The M2 protein inserts into cellular membranes. Its proton channel prevents acidification of Golgi and other vesicles, thus preventing acid-induced folding and inactivation of the HA within the cell. The HA and NA are then transported to the cell surface. Positive-sense RNA templates for each segment are produced, and the negative-sense RNA genome is replicated in the nucleus. The genomic segments associate with polymerase and NP proteins to form nucleocapsids, and the NS2 protein facilitates the transport of ribonucleocapsids into the cytoplasm, where they interact with the M1 protein-lined plasma membrane sections containing M2, HA, and NA. The virus buds selectively from the apical (airway) surface of the cell as a result of the preferential insertion of the HA in this membrane. Virus is released approximately 8 hours after infection.
5. The mRNAs are translated into protein in the cytoplasm. The HA and NA glycoproteins are processed by the endoplasmic reticulum and Golgi apparatus. The M2 protein inserts into cellular membranes. Its proton channel prevents acidification of Golgi and other vesicles, thus preventing acid-induced folding and inactivation of the HA within the cell. The HA and NA are then transported to the cell surface. Positive-sense RNA templates for each segment are produced, and the negative-sense RNA genome is replicated in the nucleus. The genomic segments associate with polymerase and NP proteins to form nucleocapsids, and the NS2 protein facilitates the transport of ribonucleocapsids into the cytoplasm, where they interact with the M1 protein-lined plasma membrane sections containing M2, HA, and NA. The virus buds selectively from the apical (airway) surface of the cell as a result of the preferential insertion of the HA in this membrane. Virus is released approximately 8 hours after infection.
6. Pathogenesis and Immunity Influenza initially establishes a local upper respiratory tract infection (Box 57-2). To do so, the virus first targets and kills mucus-secreting, ciliated, and other epithelial cells, causing the loss of this primary defense system. NA facilitates the development of the infection by cleaving sialic acid (neuraminic acid) residues of the mucus, thereby providing access to tissue. Preferential release of the virus at the apical surface of epithelial cells and into the lung promotes cell-to-cell spread and transmission to other hosts. If the virus spreads to the lower respiratory tract, the infection can cause severe desquamation (shedding) of bronchial or alveolar epithelium down to a single-cell basal layer or to the basement membrane. BOX 57-2 Disease Mechanisms of Influenza A and B Viruses Virus can establish infection of the upper and lower respiratory tract. Systemic symptoms are caused by the interferon and cytokine response to the virus. Local symptoms result from epithelial cell damage, including ciliated and mucus-secreting cells. Interferon and cell-mediated immune responses (natural killer and T cells) are important for immune resolution and immunopathogenesis. Infected people are predisposed to bacterial superinfection because of the loss of natural barriers and exposure of binding sites on epithelial cells. Antibody is important for future protection against infection and is specific for defined epitopes on hemagglutinin (HA) and neuraminidase (NA) proteins. The HA and NA of influenza A virus can undergo major (reassortment: shift) and minor (mutation: drift) antigenic changes to ensure the presence of immunologically naïve, susceptible people. Influenza B virus undergoes only minor antigenic changes. In addition to compromising the mucociliary defenses of the respiratory tract, influenza infection promotes bacterial adhesion to the epithelial cells. Pneumonia may result from a viral pathogenesis or from a secondary bacterial infection. Influenza may also cause a transient or low-level viremia but rarely involves tissues other than the lung.Influenza infection leads to an inflammatory cell response of the mucosal membrane, which consists primarily of monocytes and lymphocytes and few neutrophils. Submucosal edema is present. Lung tissue may reveal hyaline membrane disease, alveolar emphysema, and necrosis of the alveolar walls (Figure 57-3).Interferon and cytokine responses, which peak at almost the same time as virus in nasal washes, may be sufficient to control the infection, and are responsible for the systemic "flulike" symptoms. T-cell responses are important for effecting recovery and immunopathogenesis, but antibody, including vaccine-induced antibody, can prevent disease. As for measles, influenza infection depresses macrophage and T-cell function, hindering immune resolution. Of interest, recovery often precedes detection of antibody in serum or secretions.Protection against reinfection is primarily associated with the development of antibodies to HA, but antibodies to NA are also protective. The antibody response is specific for each strain of influenza, but the cell-mediated immune response is more general and is capable of reacting to influenza strains of the same type (influenza A or B virus). Antigenic targets for T-cell responses include peptides from HA but also from the nucleocapsid proteins (NP, PB2) and M1 protein. The NP, PB2, and M1 proteins differ considerably for influenza A and B but minimally between strains of these viruses; hence T-cell memory may provide future protection against infection by different strains of either influenza A or B.
7. Protection against reinfection is primarily associated with the development of antibodies to HA, but antibodies to NA are also protective. The antibody response is specific for each strain of influenza, but the cell-mediated immune response is more general and is capable of reacting to influenza strains of the same type (influenza A or B virus). Antigenic targets for T-cell responses include peptides from HA but also from the nucleocapsid proteins (NP, PB2) and M1 protein. The NP, PB2, and M1 proteins differ considerably for influenza A and B but minimally between strains of these viruses; hence T-cell memory may provide future protection against infection by different strains of either influenza A or B.