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ORTHOMYXOVIRUSES

ORTHOMYXOVIRUSES. Orthomyxoviridae - Important Aspects. Enveloped, -strand, segmented RNA Segmentation allows random assortment in mixed infections Pandemics approximately every 15 years due to antigenic shift Yearly epidemics due to antigenic drift

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ORTHOMYXOVIRUSES

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  1. ORTHOMYXOVIRUSES

  2. Orthomyxoviridae - Important Aspects • Enveloped, -strand, segmented RNA • Segmentation allows random assortment in mixed infections • Pandemics approximately every 15 years due to antigenic shift • Yearly epidemics due to antigenic drift • Multiplication sensitive to Amantadine and Actinomycin D

  3. Properties • Enveloped, helical nucleocapsid • Contains negative sense RNA in 8 segments • 8 pieces for types A and B • 7 pieces for type C • Envelope glycoproteins form two types of spikes

  4. HA - hemagglutinin NA - neuraminidase helical nucleocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex M1 protein Structure of Virion 100 nm Influenza virions are SMALL. The average eukaryotic cell diameter is 10,000 nm (10 microns), which is 100 times bigger than the influenza virion diameter. http://www.med.sc.edu:85/pptvir2002/INFLUENZA-2002.ppt

  5. Types A & B 3 IMPs HA NA M1 8 Segments of RNA Responsible for epidemics & pandemics Type C 1 IMP HEF Serves functions of both HA and NA 7 Segments of RNA Causes only mild infections Influenza Subtypes • Influenza strains are subtyped A, B, or C based on the relatedness of the matrix (M1) and nucleoprotein (NP) antigens • All 3 subtypes can infect human, subtype A can also infect other mammals and birds • Within each subtype, there are many variant strains

  6. Subtype Viral Structure/Carriers Type A Type B • Humans • Swine • Birds • Horses • Seals • Humans Type C • Humans • Swine http://www-ermm.cbcu.cam.ac.uk/01002460a.pdf

  7. Influenza A virus subtype • Influenza A virus subtyped based on the relatedness of the hemagglutinin (HA) neuraminidase (NA) antigens. • H (1-16) N (1-9) • H1N1, H1N2,and H3N2 are the influenza A virus subtype which infect Human

  8. A/Moscow/21/99/H3N2 Subtype NP & MI Geographic Origin Strain Number Year of Isolation HA & NA Sub-strain Nomenclature • 3 Subtypes, coupled with variance of the antigenicity of surface proteins (HA & NA) and the long history of influenza epidemics necessitate a nomenclature system to catalogue each strain.

  9. Influenza A virus subtype

  10. Envelope Glycoproteins • Hemagglutinin ( H antigen) • Required for viral attachment to neuraminic acid receptors on susceptible cells • Stimulates formation of protective (neutralizing) antibody • Agglutinates erythrocytes in vitro • Important diagnostic tool

  11. Envelope Glycoproteins, cont. • Neuraminidase (N antigen) • Facilitates release of newly formed virus particles from cell • Removes neuraminic acid from cell and permits dissemination of viruses • Stimulates production of protective antibodies

  12. Replication • Viral RNA polymerase is part of nucleocapsid and associated with viral genome segments • After entry, the ribonucleoprotein is transported to the nucleus • Host cell provides primer (cap) from 5’ terminal regions of cell mRNA for synthesis of viral mRNA

  13. Replication of Orthomyxovirus RNA

  14. Replication, cont. • Viral mRNAs migrate to cytoplasm • Each mRNA codes for a different protein • Viral proteins and viral genomic RNA segments assemble in nucleus • Newly assembled viral nucleocapsids migrate to cytoplasm and pick up envelope as they bud out of the cell.

  15. Replication Cycle of Orthomixoviruses

  16. Epidemiology of Influenza A • Viruses can undergo frequent changes due to recombination, reassortment, insertions and point mutations • Antigenic drift • Antigenic shift occurs every 8-10 yrs • Minor antigenic changes favor persistence of the viruses in the population and allow recombination that can eventually lead to severe epidemics and/or pandemics

  17. Antigenic drift • Antigenic differences can result from changes in one amino acid • Can involve any antigenic protein • Can occurs every year

  18. Antigenic shift • Occurs every 8-10 yrs • Major antigenic change of either H or N antigens or both H and N • Occurs by gene reassortment after simultaneous infection of a cell with two different viruses • Three different H proteins and 2 major N proteins have evolved

  19. Minor changes in the antigenic character Mutation rate highest for type A, lowest for type C Most meaningful mutations occur in HA1 protein Genetic Reassortment (HA & NA) Antigenic Drift http://www.biotech.ubc.ca/db/TEACH/BANK/PPT/flu2.ppt

  20. Antigenic Shift • Phylogenic evolution that accounts for emergence of new strains of virus • Immunologically distinct, novel H/N combinations • Genetic reassortment between circulating human and animal strains is responsible for shifts • Segmented genome facilitates reassortment • Only been observed in type A, since it infects many species

  21. Diagram of Antigenic Shift

  22. Timeline of Influenza Type A Pandemics

  23. INFLUENZA • severe respiratory disease • 20-50 million respiratory illnesses each year in the U.S. • 30 million visits to physicians, 200,000 hospitalizations • 20,000 deaths • new influenza virus strains associated with severe pandemics and high mortality.

  24. Pathogenesis • Influenza is a localized respiratory disease -not a gastrointestinal disease • Short incubation period - 2days • Localized infection of URT • Cilial damage and cell desquamation • Inflammatory response • Viral toxicity - proteins enter blood

  25. Clinical Responses • Acute Symptoms last one week • Abrupt onset of fever, myalgia, headache and non-productive cough • Fatigue and weakness can last 2-3 weeks. • Infected individual predisposed to bacterial infections – Staphylococcus, Streptococcus, Hempohilus • Other complications - Reyes Syndrome • Immunity dependent upon localized anti-viral secretory IgA ( strain specific) • Develop long lasting circulating anti-viral IgG

  26. Is it a cold or the flu? • Symptoms Cold Flu • Fever:Rare Characteristic,high (38- 40 °C),lasts 3 –4 days • Headache:Rare Prominent • General Aches: Pains Slight Usual Often severe • Fatigue: Quite mild Can last up to 2 –3 weeks • Stuffy Nose:Common Sometimes • Sneezing:Usual Sometimes • Sore Throat:Common Sometimes • Chest Discomfort: Mild to moderateCommon:can become hacking cough severe

  27. Complications – “Superinfection” • A bacterial “superinfection” can develop when the influenza virus infects the lungs. • The result? • The bacteria that live in the nose and throat can descend to the lungs and cause bacterial pneumonia. • Who is most at risk? • People over 50, infants, those with suppressed immune function or chronic diseases. • Other complications include bronchitis, sinusitis and ear infections. http://www.ecureme.com/atlas/version2001/atlas.asp

  28. Laboratory Diagnosis • Virus isolation and growth in embryonated eggs • Direct immunofluorescence • PCR , RT-PCR • Serodiagnosis • Four-fold or greater increase in hemagglutination inhibition antibody titers between acute and convalescent specimens

  29. Prevention and Treatment • Amantidine hydrochloride • Rimantadine • Inactivated viruses used as vaccines • Short duration • Yearly changes in circulating viruses • Problems = egg allergies and possible association with Guillain-Barre syndrome • Attenuated and component vaccines are under development

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