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Notes on Flu

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MICB 202
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Micb 202: INFLUENZAA • Influenza A o Severe lower respiratory infection o Spread by aerosols: 1 droplet=100,000-1,000,000 virions o 18-72 hr incubation • Criteria for outbreak o Greater than 10% absent than expected level o 2 or more cases in 7 days with at least 1 lab confirmed test • Naming influenza strains • (geographic origin is where it is first isolated, not necessarily where the virus began) • Is a ORTHOMYXOVIRUS o Enveloped, -RNA genome o Wide variety of hosts o Pleomorphic (many shapes)—no true capsid o Has envelope, nucleocapsid, genome o • Genetic material: o 8 separate RNA pieces, all (-) o Each codes for dif gene product  6 code for a single protein, 2 code for more o Each strand covered with protein=RNP=nucleocapsid o Each RNP=RNA coated with NP protein, packaged with own RDRP complex • How influenza A enters cells o Virus receptor=sialic acid=residue on membrane GPs o Animals have different versions of sialic acid o Antireceptor=hemagglutinin  Different variants will determine the virus host range • Host range o Depends on antireceptor o Flu A has subtypes based on hemagglutinin and neuraminidase proteins  16 HA, 9NA • Many dif combos are possible o Natural host=dabbling ducksbenign disease  But is adaptive to infect others  Pandemic if species has no immunity  Viral Lectures: Flu continued • Attachement+ entry o Respiratory tract o HA binds to SA on host cellsentire virus enters cell via receptor-mediated endocytosis • HA is present as HA0 on virus, needs to be cleaved into HA1 and HA2 by Clara tryptase (secreted by Clara cells of respiratory tract) to reveal fusion peptide which is between HA2 and HA1 • Inside the endosome, pH is low, which causes change in conformation of HA to allow it to insert into endosome membrane allowing fusion and release of genome into the cytoplasm which then homes into the nucleus o The cleavage needs to have occurred by the time the virus is in the endosome • Recall: RNA of flu is wrapped in NPs and each comes with an RDRP • Synthesize 2 types of RNA o 1. Incomplete=mRNA for protein synthesis  Made early on  Steal 5’ caps from cellular mRNA, polyA tail also from host?  Exported into cytoplasm to ribosome. Happens for all 8 segments. 2 segments require splicing. mRNA for HA and NA proteins on ER ribosome o Complete=made only after accumulation of porteins  Uses NP as primer  Is template to replicate genome  No cap o Both use RDRP complex and use –RNA as template • RNA dependent RNA polymerase has 2 conformations o RDRP conformation for making mRNA (default) changes to replicating genome conformation when high levels of [NPs] • Assembly of progeny o HA, NA inserted into host cell plasma membrane o Genomic RNA coated with NP in nucleus, and associates with RDRP complex to form RNPgoes to cell membrane to assemble with other proteins o Always arrange in same daisy pattern of 7 rods around a central core o Virus buds and NA digests sialic acid at host cell surface to prevent re- infection o Viral replication results in destruction of host mRNA and depletes reserves of a.a. and nucleotides. How do new Flu strains arise? • Antigenic drift: random point mutations in genetic materialvariations in seasonal flu o Differences of our MHC affinities to epitopes that have single a.a variations • Antigenic shift: 2 dif strains infect same cell to cause reassortment of segments o Less frequent. Result in new strain that no one is immune too. Can cause pan
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