{"id":2475,"date":"2018-10-20T17:51:40","date_gmt":"2018-10-20T17:51:40","guid":{"rendered":"https:\/\/www.mybiosource.com\/learn\/?p=2475"},"modified":"2023-03-13T13:26:18","modified_gmt":"2023-03-13T13:26:18","slug":"influenza-series-how-does-influenza-virus-act","status":"publish","type":"post","link":"https:\/\/www.mybiosource.com\/learn\/influenza-series-how-does-influenza-virus-act\/","title":{"rendered":"Influenza Series: How does Influenza virus act?"},"content":{"rendered":"\n\n\n
\n

Table of Contents<\/u><\/strong><\/h3>\n

1. Introduction<\/strong><\/a>
\n2. Influenza Virus Morphology<\/strong><\/a>
\n\u2022 Pleomorphic with spherical or filamentous morphology
\n\u2022 Enveloped virus with outer lipid membrane and embedded proteins
\n3. Influenza Virus Genome<\/strong><\/a>
\n\u2022 Segmented negative-sense RNA core
\n\u2022 Eight RNA segments
\n\u2022 Replication in the nucleus
\n4. Influenza Virus Host Interaction<\/strong><\/a>
\n\u2022 Virus entry into the cell via recognition of sialic acid receptor
\n\u2022 Engagement of HA protein triggers endocytosis
\n\u2022 Release of viral genome into the cell
\n\u2022 Host immune response against virus
\n\u2022 Vaccination as the most effective way to control influenza infection.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The influenza<\/span> virus has been a focus of intensive investigation in many disciplines of modern biology. All influenza<\/span> viruses<\/span> are characterized by a segmented negative-sense RNA<\/span> core surrounded by a lipid envelope. The most effective way to control influenza<\/span> infection is vaccination and designing of a successful vaccine needs a proper understanding of the virus morphology and its host interaction.<\/p>\n

The influenza<\/span> virus particles are pleomorphic<\/span> with spherical or filamentous morphology, or both. The spherical or filamentous morphology varies with the different number of passages. Like in clinical isolates filamentous particles outnumber the spherical particles as they undergo a limited number of passages in eggs or cell culture, whereas laboratory strains consist almost exclusively of spherical virions (80\u2013120 nm in diameter) as they are extensively passaged. It is an enveloped virus with the following \u2013<\/p>\n

— An outer layer is a lipid membrane<\/span> which is taken from the host cell in which the virus multiplies.<\/p>\n

—- Inserted into the lipid membrane<\/span> are \u2018spikes,\u2019 which are proteins<\/span> \u2013 precisely glycoproteins<\/span>, because they consist of the protein linked to sugars \u2013 known as HA<\/span> (hemagglutinin<\/span>) and NA (neuraminidase<\/span>). These are the proteins<\/span> that determine the subtype of influenza<\/span> virus (A\/H1N1<\/span>, for example). The HA<\/span> spikes are rod-shaped, whereas the NA spikes resemble mushrooms with slender stalks. The HA<\/span> and NA are essential in the immune response against the virus; antibodies (proteins<\/span> made by us to combat infection) against these spikes may protect against infection. The NA protein is the target of the antiviral<\/span> drugs Relenza<\/span> and Tamiflu<\/span>. HA<\/span> has a propensity to bind and aggregate red blood cells, as its name implies. This property of HA<\/span> is exploited for the detection of influenza<\/span> virus. Importantly, HA<\/span>, which is a trimer, is the viral protein that recognizes the cellular receptor<\/span> for the entry.<\/p>\n

—-Also embedded in the lipid membrane<\/span> is the M2 protein, which acts as an ion channel. The integral homo-tetrameric M2 membrane protein<\/span>, although abundantly expressed at the surface of virus-infected cells, is nonetheless a relatively minor component of virions. It is the target of the antiviral<\/span> adamantanes \u2013 amantadine<\/span> and rimantadine<\/span>.<\/p>\n

—- Beneath the lipid membrane<\/span> is a viral protein called M1, or matrix protein<\/span>. This protein, which forms a shell, gives strength and rigidity to the lipid envelope. Cryoelectron microscopic studies suggest that the M1 can modify the lipid bilayer, causing the viral envelope<\/span> to thicken. M1 is the primary determinant of virus budding.<\/p>\n

Within the interior of the virion are the eight RNA<\/span> segments. It is also called a \u201csegmented genome\u201d or \u201csplit genome,\u201d because the genome is split into eight segments. The multiplicity of the genome is attributable to the emergence of viral variants through genetic recombination<\/span>. Each RNA<\/span> segment is a single-strand<\/span> RNA<\/span> 0.9 – 2.3 kb in length. It is also called \u201cvRNA.\u201d Being a negative-strand RNA<\/span>, it is neither capped at the 5 end or polyadenylated at the 3 end. Instead, it has a triphosphate group at the 5 end (i.e., pppAp—) and a hydroxyl group at the 3 end (i.e., CUUUUGCU-OH-30 ). These are the genetic material of the virus; they code for one or two proteins<\/span>. Each RNA<\/span> segment consists of RNA<\/span> joined with several proteins<\/span> – PB1, PB2, PA, NP. The interior of the virion also contains another protein called NEP. Unlike other RNA<\/span> viruses<\/span>, influenza<\/span> viral genome replication occurs in the nucleus. Hence, the viral proteins<\/span> essential for viral genome replication needs to be imported into the nucleus. For instance, NP (nucleocapsid protein), RdRp (PB1, PB2, PA subunit), NS1<\/span>, and NEP are imported to the nucleus. The nucleocapsids are constituted by vRNA, NP, and RdRp (i.e., PB1, PB2, PA). This RNP complex now enters the nucleus via the nuclear pore. Most RNA<\/span> polymerases do not need an RNA<\/span> primer for transcription<\/span> initiation (i.e., de novo initiation). However, influenza<\/span> viral RdRp needs a primer for transcription<\/span> initiation.
\nMoreover, influenza<\/span> virus RdRp steals a capped RNA<\/span> fragment from the cellular mRNAs and utilizes them as primers. Viral RdRp is composed of 3 subunits: PB1 acts as an RNA<\/span> polymerase<\/span>, PB2 exhibits cap-binding ability, and PA exhibits endonuclease activity. In particular, the endonuclease activity of PA cleaves a capped RNA<\/span> fragment from the 5 end of cellular mRNAs, which is then used as a primer for viral mRNA transcription<\/span>. This process is referred to as \u201ccap-snatching.\u201d Unlike cellular mRNA, the poly (A) tail is copied from the template during transcription<\/span>. A short run of U residues (i.e., U6 7) at the 50 end of vRNA are repeatedly copied to make the tail (see Fig. 15.2B). In other words, poly (A) tail at the 3 end of viral mRNA is added via template-dependent manner. The mechanism is called \u201cstuttering.\u201d Viral mRNA sequences are not complementary to the 5 end of vRNA because the viral transcription<\/span> is terminated after polyadenylation. Resulting viral mRNAs are exported to the cytoplasm<\/span> and used as mRNA for the viral protein synthesis<\/span>.<\/p>\n

 <\/p>\n

Influenza virus enters the cell via recognition of the cellular receptor<\/span>, a sialic acid. The engagement of the HA<\/span> timer to a sialic acid moiety of glycan on the cell membrane triggers endocytosis<\/span>. The sialic acids<\/span> are linked to galactose via either an \u03b1-2,3 linkage or an \u03b1-2,6 linkage. The HA<\/span> of human influenza<\/span> virus prefers to bind to an \u03b1-2,6 linkage, while HA<\/span> of avian<\/span> influenza<\/span> virus prefers to bind to an \u03b1-2,3 linkage. Glycans in human upper respiratory tracts are largely composed of \u03b1-2,6 linkage. This is the reason why human infection of avian<\/span> influenza<\/span> virus is restricted. Upon endocytosis<\/span>, the virus particles are located inside the endosome. The acidic pH<\/span> in the endosome triggers membrane fusion between the two membranes. Via the M2 ion channels, protons are imported inside of the viral envelope<\/span>, and the resulting lower pH<\/span> induces a conformational change of HA<\/span> trimer such that an embedded fusion peptide<\/span> domain becomes unfolded and activated. This activated fusion peptide<\/span> triggers membrane fusion between two membranes, and as a result, the nucleocapsids inside the envelope are released to the cytoplasm<\/span>.
\nNowadays the focus of the influenza<\/span> study has shifted to understand the interplay between influenza<\/span> viruses<\/span> and their host cells. Earlier studies, however, focused on the essential functions of viral proteins<\/span> in the viral life cycle. In genome-wide RNA<\/span> interference (RNAi) studies, double-stranded<\/span> RNA<\/span> molecules are used for the homology-dependent suppression of cellular gene activity to identify genes that are critical for the influenza<\/span> viral life cycle 1-4.
\nIn other studies, yeast two-hybrid analyses, proteomics approaches, gene-expression<\/span> profiling studies, and mass spectrometry<\/span> analyses have been used to identify cellular factors that interact with influenza<\/span> virus proteins<\/span> 5-10. These studies have identified a significant number of cellular factors that may interact with influenza<\/span> virus proteins<\/span>; however, follow-up studies are largely missing that assess the biological significance of the respective cellular protein for the viral life cycle.<\/p>\n

References<\/strong><\/p>\n

    \n
  1. Hao L, Sakurai A, Watanabe T et al. (2008) Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454: 890\u2013893.<\/li>\n
  2. Brass AL, Huang IC, Benita Y et al. (2009) The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139: 1243\u20131254<\/li>\n
  3. Karlas A, Machuy N, Shin Y et al. (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza<\/span> virus replication. Nature 463: 818\u2013822.<\/li>\n
  4. Konig R, Stertz S, Zhou Y et al. (2010) Human host factors required for influenza virus replication. Nature 463: 813\u2013817.<\/li>\n
  5. Billharz R, Zeng H, Proll SC et al. (2009) The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways. Journal of Virology 83: 10557\u201310570.<\/li>\n
  6. Chakrabarti AK, Vipat VC, Mukherjee S et al. (2010) Host gene expression profiling in influenza A virus-infected lung epithelial (A549) cells: a comparative analysis between highly pathogenic and modified H5N1<\/span> viruses. Virology Journal 7: 219.<\/li>\n
  7. Mayer D, Molawi K, Martinez-Sobrido L et al. (2007) Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. Journal of Proteome Research 6: 672\u2013682.<\/li>\n
  8. Reemers SS, Groot Koerkamp MJ, Hostege FC et al. (2009) Cellular host transcriptional responses to influenza A virus in chicken tracheal organ cultures differ from responses in vivo<\/span> infected trachea. Veterinary Immunology and Immunopathology 132: 91\u2013100.<\/li>\n
  9. Shapira SD, Gat-Viks I, Shum BO et al. (2009) A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139: 1255\u20131267<\/li>\n
  10. Zhu W, Higgs BW, Morehouse C et al. (2010) A whole genome transcriptional analysis of the early immune response induced by live attenuated and inactivated influenza vaccines in young children. Vaccine 28: 2865\u20132876.<\/li>\n<\/ol>\n

     <\/p>\n","protected":false},"excerpt":{"rendered":"

    Table of Contents 1. Introduction 2. Influenza Virus Morphology \u2022 Pleomorphic with spherical or filamentous morphology \u2022 Enveloped virus with outer lipid membrane and embedded proteins 3. Influenza Virus Genome \u2022 Segmented negative-sense RNA core \u2022 Eight RNA segments \u2022 Replication in the nucleus 4. Influenza Virus Host Interaction \u2022 Virus entry into the cell […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"off","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"categories":[31],"tags":[52],"class_list":["post-2475","post","type-post","status-publish","format-standard","hentry","category-news","tag-influenza"],"_links":{"self":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts\/2475","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/comments?post=2475"}],"version-history":[{"count":0,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts\/2475\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/media?parent=2475"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/categories?post=2475"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/tags?post=2475"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}