The immune system is blind sided by these changes so

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“Mixing Vessels.” • The Immune System is Blind-sided by these Changes, so you ʼ ll probably catch the Flu Impact • Since Influenza Epidemics involve very large Numbers of Individuals, the Number of Deaths can be surprising (~55 Million in 1918)
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Influenza Page 5 Type A Influenza Virus 100 nm Diameter, 13.2 Kb Negative Sense Splint RNA Virus • Each Particle consists of: - “Shrink-Wrapped” Lipid Bilaer Envelope containing: • Hemagglutinin (HA) - Hemagglutinin is a Rod-shaped Trimer. - Each Virus Particle contains approximately 500 HA Trimers. There are 16 different Types of HA. All 500 of these HAs will be the same Type of HA. • Neuraminidase (NA) - Neuraminidase is a Mushroom Shaped Tetramer - Each Virus Particle contains approximately 100 NA Tetramers There are nine different Types of NA. All of these NAs will be the same Type of NA. • Membrane Protein (M 2 ) [M= “Membrane”] - M 2 Tetramers form Transmembrane Proton Channels that promote release of Nucleocapsids into the Cytoplasm - Matrix Protein (M 1 ) [M= “Matrix”] - Eight Helical Nucleocapside • Each with its own Single Strand of Negative Sense RNA protected by Nucleoprotein (NP) - Each contains its own Set of RNA Polymerase Components (PA, PB1, PB2) - 5´ and 3´ Ends of RNA bind to PB1
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Influenza Page 6 Influenza Virus Entry • Neuraminidase (NA) digests Mucous on the Surface of Respiratory Cells, exposing the Cell Membrane • Hemagglutinin (HA) binds to Sialic Acid Residues on Surface Glycoproteins - HA binding induces Endocytosis into Vesicles • These Vesicles are delivered to Endosomes • Acidification of Endosomes causes a Conformational Change in HA - This exposes the Fusion-Promoting Region on HA • Virus Envelope and Endosome Membrane Fuse At the same Time an Ion Channel formed by M 2 Tetramers (G= four) promotes Acidification inside the Virus Particle. This weakens the Interactions of M 1 ʼ s and NP ʼ s, which allows the Nucleocapsids to be released into the Cytoplasm • The 8 Helical Nucleocapisids go to the Nucleus - NP and Polymerase Components contain Nuclear Localization Signals Influenza Virus mRNA Synthesis • Influenza Transcriptase uses Negative Sense Influenza Genome RNA Segments as Template Primed RNA Synthesis - PA, PB1 and PB2 function as a trimeric Transcriptase Complex • PB2 binds to the Cap at the 5´ End of a Host Cell mRNA (“Cap Snatching”) • PB1 cleaves this Host Cell mRNA 10-13 Bases from the Cap (at an A) and uses this Capped RNA Fragment as a Primer - The 3´ A of the Host Cell RNA Fragment is bound to the 3´ U of the Influenza Genome RNA • PB1 acts as an RNA Polymerase (“Primed RNA Synthesis”) The Function of PA during Transcription is Unknown. - Poly-A Tails are added by repeated Slippage (“Chattering”) of PB1 over a short Poly-U Tract ~20 Bases from the 5´ End of the Genome • So PB1 polymerizes a slightly truncated Copy of the Genome • Resultant Influenza mRNA Molecules are transported to the Cytoplasm
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Influenza Page 7 Influenza Virus Protein Synthesis • Most Influenza Virus Proteins are made on “Free” Ribosomes in the Host Cell Cytoplasm - PB1, PB2, PA, NP, M 1 NS 1 , NS 2 • NS 1
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