Influenza viruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics

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Virginia Patterson
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1 Influenza viruses Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics

2 Virion Enveloped particles, quasi-spherical or filamentous Diameter nm Envelope is derived from host plasma membrane by budding Compact helical nucleocapsids

3 Genome Linear single-stranded RNA, negative sense Six to eight different segments Total genome length kb

4 Genes and proteins Each genome segment codes for one or two proteins Envelope glycoproteins: hemagglutinin (HA) and neuraminidase (NA) Integral membrane protein (M2) Matrix protein (M1) Nucleocapsid protein (NP) Three RNA pol proteins (PA, PB1 and PB2) Nonstructural protein (NS1) Minor structural protein (NS2) Additional nonstructural protein (PB1-F2)

5 Viruses and Hosts Orthomyxoviridae from the Greek ortho (correct or normal) and myxa (mucus) Two additional genera: Thogotovirus (transmitted by ticks) and Isavirus (infects fish, particularly salmon) Influenza types A, B and C: hosts include birds, various mammals and humans

6 Diseases Symptoms include: High fever, sore throat, cough, headache, muscular pain Can be fatal in elderly, infants and chronically ill, often by secondary bacterial infections In 1918, an influenza pandemic killed 20 million worldwide A new pandemic strain spread worldwide in 2009 Emerging avian influenza virus strains threaten domestic fowl and another possible human pandemic

7 Diseases Influenza viruses cause serious acute disease in humans, and occasional pandemics Influenza was responsible for one of the worst human epidemics since the plague The Spanish flu of caused a pandemic that killed more than 20 million people

8 Diseases Influenza virus infections of the respiratory tract can lead to secondary bacterial infections Virus initially infects and causes a loss of the ciliated epithelium and disrupts mucociliary flow Virus induces production of interferons and cytokines

9 Genome Orthomyxoviruses are negative-strand RNA viruses with segmented genomes Have six to eight segments individually wrapped in helical nucleocapsids Enclosed in a lipid membrane

10 Genes and proteins Eight influenza virus genome segments code for a total of 11 different viral proteins Nine of the proteins are packaged into viral particles

11 Genes and proteins

12 Hemagglutinin protein binds to cell receptors and mediates fusion of the envelope with the endosomal membrane Hemagglutinin protein binds to sialic acid residues on muco-proteins HA can agglutinate red blood cells which is the basis for the hemagglutination assay HA is a type I transmembrane protein

13 Cleavage of HA by cellular proteases creates a subunit containing the fusion peptide

14 M2 is an ion channel that facilitates release of nucleocapsids from the virion Allows protons to enter the interior of the virus weakening the interaction of M1 with the nucleocapsids Amantadine blocks the M2 channel

15 Nucelocapsids enter the nucleus where mrna synthesis and RNA replication occur NP protein wraps the RNA into an unusual twin helical conformation with a central loop Contain nuclear localization signals that interact with importin-α

16 Unlike other RNA viruses, orthomyxoviruses replicate in the nucleus, complicating the machinery required for viral replication

17 Capped 5 ends of cellular pre-messenger RNAs are used as primers for synthesis of viral mrnas Inhibitors of cellular RNA synthesis also block virus replication (actinomycin D, α-amanitin)

19 Viral mrnas terminate in poly(a) tail generated by stuttering transcription Two influenza A mrnas undergo alternative splicing in the nucleus Unspliced RNAs create M1 and NS1 Spliced RNAs create M2 and NS2

20 Genome replication begins when newly synthesized NP protein enters the nucleus Replication of genome requires no primer

21 Nucleocapsids are exported from the nucleus in a complex with matrix protein and NS2 The NS1 protein interferes with polyadenylation of cellular mrnas Binds to and blocks the function of: cleavage and polyadenylation specificity factor (CPSF) and poly(a)-binding protein II (PABII)

22 The NS1 protein also suppresses a variety of host cell antiviral response pathways Inhibits RIG-I Activates P13K/Akt pathway Inhibits double stranded RNA-dependent protein kinase (PKR) Inhibits 2,5 -oligo(a) synthetase/ribonuclease L

23 PB1-F2 may contribute in suppression of the host immune response Localizes to mitochondria and induces apoptosis in host immune cells

24 Viral envelope proteins assemble in the plasma membrane and direct budding of virions HA, NA, M2 are directed to plasma membrane by Golgi and accumulate in lipid rafts Exactly one copy of each genome segment is packaged

25 Neuraminidase cleaves sialic acid, the cellular receptor that binds to HA NA is a type II transmembrane protein Releases the virus from the surface of the virus-producing cell

26 Influenza virus strains vary in both transmissibility and pathogenicity Certain viral proteins have adapted to function optimally in a particular species Some HA proteins are readily cleaved by furin proteases, activating the fusion mechanism

27 Genetic variability generates new virus strains that can cause pandemics Antigenic change occurs in two ways 1. Antigenic drift: slow, continuous accumulation of point mutations 2. Antigenic shift: results from reassortment of genes during a mixed infection with two or more subtypes

28 The 1918 pandemic influenza A virus was probably not an reassortant virus Genome sequences from some previous influenza A virus strains confirm the antigenic shift hypothesis

29 Highly pathogenic avian influenza A H5N1 strains in poultry farms are a potential threat but are poorly transmitted among humans zanamivir and oseltamivir are being stockpiled in case of a pandemic

30 A new pandemic strain of influenza A virus arose by genetic shift and spread worldwide in 2009

31 Fundamental concepts Influenza viruses cause serious acute disease in humans, and occasional pandemics Influenza viruses are (-)RNA viruses whose eight segments code for 11 proteins The influenza HA protein binds to cell receptors and mediates fusion of envelope and endosomal membrane The influenza virus NS1 and PB1-F2 proteins suppress a variety of host cell antiviral responses

32 Fundamental concepts The influenza virus M2 protein is an ion channel that facilitates release of nucleocapsids from virion Influenza virus nucleocapsids travel to the nucleus, where three viral proteins direct mrna synthesis, using capped RNAs from the cell as primers, and primer-independent RNA replication Influenza virus NA protein cleaves sialic acid, releasing virus Influenza virus exhibits genetic variability by drift and shift

33 Key terms α-amanitin Actinomycin D Amantadine Antigenic drift Antigenic shift Ciliated epithelium Cytokine Double stranded RNAdependent protein kinase Epidemic Furin Fusion peptide Hemagglutination assay Hemagglutinin Importin Interferon Lipid rafts Mucociliary flow Neuraminidase Oseltamivir Pandemic Reassortment Sialic acid Type I transmembrane protein Type II transmembrane protein zanamivir

Patricia Fitzgerald-Bocarsly

FLU Patricia Fitzgerald-Bocarsly October 23, 2008 Orthomyxoviruses Orthomyxo virus (ortho = true or correct ) Negative-sense RNA virus (complementary to mrna) Five different genera Influenza A, B, C Thogotovirus