RNA Viruses PDF

Orthomyxoviridae  ORTHOMYXOVIRIDAE Genome: segmented, ss (-) RNA Pleomorphic capsid Enveloped viruses (80-120 nm) The genome of the influenza A and B viruses consists of 8...

Orthomyxoviridae  ORTHOMYXOVIRIDAE Genome: segmented, ss (-) RNA Pleomorphic capsid Enveloped viruses (80-120 nm) The genome of the influenza A and B viruses consists of 8 different segments The genome of the influenza C virus consists 7 different segments HUMAN SEASONAL INFLUENZA VIRUSES ORTHOMYXOVIRIDAE Hemagglutinin (HA) Neuroaminidase (NA) M1 (matrix) M2 (membrane) NP (nucleoprotein) NS (nuclear export) Each RNA segment is associated with the NP (RNP) and the transcriptase (RNA polymerase components: PB1, PB2, PA)  ORTHOMYXOVIRIDAE HA is a spike-shaped trimer; it is the anti- NA is a tetramer and has enzyme activity. receptor binding the sialic acid on the The NA cleaves the sialic acid on epithelial cell surface; it promotes the glycoproteins on cell surface. The cleavage fusion between the envelope and the of the sialic acid on virion HA prevents endosome; it elicits the protective clumping and facilitates the release of virus neutralizing antibody response. from infected cells. HA and NA undergo minor (“drift”) and major (“shift”) changes and the different HAs and NAs are designed H1 – H16 and N1 – N9, respectively. LIFE CYCLE 1. Viral attachment: HA binds to sialic acid 2. The virus is internalized into a coated vesicle and transferred to an endosome → acidification of the endosome → fusion of the membranes → uncoating and delivery of the nucleocapsid into the cytoplasm 3. Transcription. The transcriptase (PA, PB1, and PB2) uses host cell mRNA as a primer for viral RNA synthesis (mRNAs and positive-sense RNA templates) 4. Translation 5. The negative-sense RNA genome is replicated in the nucleus 6. Assembly. Genomic segments associate with polymerase and NP proteins to form nucleocapsids 7. The virus buds selectively from the apical (airway) surface of the cell as a result of the preferential insertion of the HA, NA in this membrane.  HOW THE FLU VIRUS CAN CHANGE: “SHIFT” AND “DRIFT” Antigenic shift: o This is an abrupt, major change in the influenza A viruses, resulting in new HA and/or new NA proteins o It is caused by reassortment between animal and human viruses o May result in the emergence of pandemic strains → when shift results in a new influenza A, most people do not have immunity Antigenic shift refers to the gene recombination occurring when influenza viruses re-assort  HOW THE FLU VIRUS CAN CHANGE: “SHIFT” AND “DRIFT” The pig may be an intermediate host for interspecies spread; the replication of all avian viruses in pigs supports this notion, as does the presence of avian-type and mammalian-type virus receptors in pigs  HOW THE FLU VIRUS CAN CHANGE: “SHIFT” AND “DRIFT” Antigenic Drift o These are small changes in the genes of influenza viruses (A and B) that happen continually over time as the virus replicate o This produces viruses that are closely related to each other and usually share the same antigenic properties o When small genetic changes accumulate over time → viruses become antigenically different and the antibodies created against the older viruses no longer recognize the “newer” virus, and the person can get sick again  INFLUENZA A SUBTYPES Strains of influenza A virus are classified by the following characteristics: Subtypes of influenza A virus are named according to H and N 16 hemagglutinin (H1-H16) subtypes 9 neuraminidase (N1-N9) subtypes Among influenza A viruses that infect humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described; the currently circulating influenza A subtypes in humans: H1N1, H3N2  INFLUENZA A SUBTYPES H1 N1 H2 N2 H3 N3 H4 N4 H1, H2, and H3 are the major subtypes of HA H5 N5 N1 and N2 are the two H6 N6 subtypes of NA H7 N7 H8 N8 H9 N9 H10 H11 H12 Aquatic birds are the H13 natural resevoir of the virus H14 H15 H16  INFLUENZA B STRAINS Strains of influenza B are designated by: (1) type (2) geography (3) date of isolation e.g., B/Colorado/06/2017 (lineage B/Victoria); B/Phuket/3073/2013-like (lineage B/Yamagata) Influenza B virus infects only humans  PATHOGENESIS When influenza virus is introduced into the respiratory tract, it attaches to and replicates in epithelial cells of both the upper and lower respiratory tract. Viral replication combined with the immune response to infection lead to destruction and loss of cells lining the respiratory tract. As infection subsides, the epithelium is regenerated, a process that can take up to a month. Cough and weakness may persist for up to 2 weeks after infection. Local symptoms result from epithelial Systemic symptoms are caused by the cell damage interferon and cytokine response to the virus  PATHOGENESIS Cells of the upper and lower respiratory tracts serves as the primary barrier  PATHOGENESIS Infection of epithelial cells that express the sialic acid receptors causes damage to the physical barrier as junctional proteins become compromised during cell death  CLINICAL SIGNS The “flu syndrome” begins with a brief prodrome of malaise and headache. The prodrome is followed by the abrupt onset of fever, chills, severe myalgias, weakness, sore throat, and a nonproductive cough. The fever persists for 3 to 8 days, unless a complication occurs. In young children: bronchiolitis, croup, otitis media, accompanied rarely by febrile convulsions. → Gastrointestinal illness, such as vomiting and diarrhea, are usually not part of influenza infections in adults but can occur in 10 to 20 % of influenza infections in children.  CLINICAL SIGNS Severe complications: 1) Primary viral pneumonia is caused by viral replication in alveolar epithelial cells 2) Secondary bacterial pneumonia is related to the the loss of natural barriers and exposure of binding sites on epithelial cells (Streptococcus pneumoniae, Staphylococcus aureus, and Hemophilus influenzae) 3) Myocarditis and pericarditis 4) Myositis 5) Encephalopathy  DIAGNOSIS OF INFLUENZA VIRUS INFECTION Molecular methods: o RT-PCR amplification of the viral genome in respiratory samples, including nasopharyngeal aspirate, tracheal aspirate, bronchoalveolar lavage o Typing and subtyping is usually available in reference centers To be performed only in severe cases/hospitalized patients  ANTIVIRAL THERAPY AGAINST INFLUENZA VIRUS Antiviral treatment should be offered only to infected patients requiring hospitalization and/or at high risk of complications ▪ Zanamivir (Relenza®) and oseltamivir (Tamiflu®) act as neuroaminidase inhibitor → prevent new viral particles from being released ▪ Amantadine and rimantadine behave as inhibitors of the viral M2 matrix protein ion channels (influenza A virus)  THE MOVING VACCINE TARGET Because influenza viruses change so rapidly, vaccines should represent the “strains of the year” → Ideally, the vaccines incorporate antigens of the A and B influenza strains that will be prevalent in the community during the upcoming winter