Intrinsic cellular defenses against virus infection

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Nathan Hines
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1 Intrinsic cellular defenses against virus infection Detection of virus infection Host cell response to virus infection Interferons: structure and synthesis Induction of antiviral activity Viral defenses against interferon responses RNA interference

2 Detection of virus infection Host cells sense virus infection with tolllike receptors and a variety of other molecular detection systems Virus binding to cell surface triggers production of cytokines like interleukin-1α Virus entry triggers interferon-stimulated genes TLRs recognize pathogen-associated molecular patterns and trigger the production of cytokines

3 Detection of virus infection

4 Detection of virus infection Several toll-like receptors recognize viral nucleic acids Cells must undergo autophagy (forming phagosomes to degrade their contents) for delivery of viral RNA to vesicles containing TLR-7

5 Detection of virus infection Other cellular proteins are also involved in recognition of viral RNAs RIG-I and MDA5 recognize viral RNAs in the cytosol

6 Detection of virus infection Viral double-stranded DNAs in the cytoplasm are recognized by at least three different cellular proteins DAI binds to bacterial, viral and mammalian DNA in the cytosol and leads to the production of interferon AIM2 and NLRP3 bind to viral dsdna and induce production of pro-inflammatory cytokines

7 Host cell response to viral infection Virus-mediated signal transduction leads to activation of cellular transcription factors Signaling molecules recruit protein kinases which then activate transcription factors Transcription factors activate genes involved in cytokine, chemokine and stress-related molecule production

8 Host cell response to viral Signal transduction following virus recognition infection

9 Host cell response to viral infection Cellular recognition of virus infection leads to production of cytokines Cytokines stimulate protective reactions in the infected host Interferons: major players in host defense against most viruses Pro-inflammatory cytokines: activate immune cells in the circulatory system Chemokines: recruit other immune cells to site of infection Anti-inflammatory cytokines: suppress the proinflammatory cytokines

10 Host cell response to viral infection

11 Host cell response to viral infection Recognition of virus infection can trigger death of infected cells Apoptosis involves the activation of caspases and is triggered by infection Extrinisic pathway: Binding of a molecule like TNFα to receptors on the cell surface Intrinsic pathway: is activated by internal stress like DNA damage or viral DNA replication

12 Host cell response to viral Intrinsic and extrinsic pathway of apoptosis infection

13 Host cell response to viral Other antiviral signal transduction pathways involve inflammasomes infection Caspase-1 is involved in the regulation of cytokine maturation and is activated by recognition of viral nucleic acid by AIM2 and NLRP3 Another cell death pathway, pyroptosis, is dependent on caspase-1 and proinflammatory cytokines

14 Host cell response to viral infection Cellular sensor proteins activate caspases and cytokines

15 Interferons: structure and synthesis Virus infected cells secrete interferons, which protect nearby cells against viral infection Discovered by studies of viral interference, where infection with one virus can interfere with subsequent infection by another virus

16 The interferon system Interferons: structure and synthesis

17 Interferons: structure and synthesis Interferons are a first line of host defense against viruses: however, therapeutic use has been limited Therapeutic use of cloned interferon has many unpleasant side effects and short-lived antiviral effects

18 Interferons: structure and synthesis Interferons α, β, γ, and λ are made by different cells, bind to different receptors, and have distinct functions

19 Interferons: structure and Transcription of interferon genes is activated by virus infection or doublestranded RNA synthesis Transcriptional activation occurs by binding of transcription factors to interferon gene enhancers

20 Induction of antiviral activity Interferon signal transduction is carried out via the Jak-Stat pathway

21 Induction of antiviral activity Antiviral activities induced by interferons The Mx proteins: interferes with transcription of influenza and other RNA viruses 2,5 -oligo(a) synthetase: activated by binding to dsrna and activate ribonuclease L which degrades both viral and cellular mrnas Double-stranded RNA-dependent protein kinase (PKR): activated by dsrna then phosphorylates a variety of cell proteins

22 Induction of antiviral activity Antiviral activity directed by 2,5 -oligo(a) synthetase and ribonuclease L

23 Induction of antiviral activity Mechanism of antiviral activity directed by PKR

24 Induction of antiviral Interferons have diverse effects on the immune system activity Interferon-γ stimulates the development and actions of immune effector cells Interferons-α and β play a more limited role in modulating the adaptive immune response

25 Viral defenses against interferon responses Viruses have developed numerous strategies to evade the interferon response Inhibition of PKR activity Inhibition of production and activity of interferon Interfere with signaling pathways

26 Viral defenses against interferon responses

27 Viral defenses against interferon responses

28 RNA interference Small interfering RNAs are involved in combating virus infections in plants and invertebrates RNA interference is initiated by the dsrnaspecific ribonuclease III enzyme Dicer Dicer cleaves dsrna into small interfering RNAs (sirnas) which are then bound by RNA-induced silencing complex (RISC) RISC then cleaves any complementary RNA

29 RNA interference Micro RNAs are used to control gene expression in vertebrates Micro RNAs (mirnas) is used in a similar manner to inhibit translation or degrade mrna Viruses also encode mirnas that target both viral and cellular RNA species

30 RNA interference RNA interference Micro RNAs

31 Fundamental concepts Toll-like receptors and other cellular pattern recognition receptors sense viral infections by binding to viral nucleic acids and glycoproteins Recognition of viral nucleic acids, particularly dsrna, leads to the activation of transcription factors including interferon regulatory factors (IRFs) and NFκB Activated IRFs and NFκB induce the production and secretion of cytokines and interferons by virus-infected cells Interferons-α, -β, and λ are expressed by most cell types, whereas interferon-γ is expressed by activated NK cells and T lymphocytes

32 Fundamental concepts Upon binding to receptors on the cell surface, interferons activate the Jak-Stat signal transduction cascade and induce transcription of a large number of interferonstimulated genes Proteins coded by the interferon-stimulated genes block virus transcription, translation and spread In response to viral infection, cytokine signaling, and sensing of intracellular stress can lead to apoptosis, programmed cell death Plants and invertebrates do not express interferon, but instead use RNA interference to fight against viral infection

Reoviruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics

Reoviruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics Reoviruses Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics Virion Naked icosahedral capsid (T=13), diameter 60-85 nm Capsid consists of two or three concentric protein