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Chapter 3: Viruses 第三章:病毒 - 非细胞型生物的形态构造 Thai dogs carry bird-flu virus, but will they spread it? • • NATURE Vol 439: 773 (16 February 2006) Vaccine? China! Bacteriophage噬菌体 T4 & lambda Of ancient origin Avian Influenza H5N1 - No. 1 threaten to human How H5N1 works? What is Virus? • • Basically a form of genetic information insures continued survival Reproduces DNA/RNA within living cells utilizing mechanisms of cells Diagram of Five Kingdoms Viruses are… • Acellular 无细胞的 – Pass the bacteria-proof filter • Obligate intracellular parasites专性细胞内寄生 – No ATP generating system – No Ribosomes or Protein Synthesis • Can be CRYSTALLIZED 结晶: life? Filtration of a mixture of bacteria and viruses Structure: Bacteria vs Virus Major difference between virus & prokaryotes Content • • Virus: morphology & replication真病毒形态构造和复制 Subvirus 亚病毒 • Virus and the application Relative size of viruses & bacteria Critical Thinking • Do you think bacteria as small as viruses will ever be discovered? Typical Structure of Virus 病毒的典型构造 • Viron (virus particle) 病毒颗粒 • Core 核心: nucleic Acid 核酸 – Capsid 衣壳: coat Protein – Capsomer 衣壳亚基 – Structural/catalytic proteins – Binding sites of antigen – Envelope 包膜: some viruses – Binding Sites (spike) Naked or Enveloped Virus 裸露或包膜的病毒 Types of Viral Nucleic Acid 病毒核酸类型 • DNA or RNA: Never both – – – – – Animal virus: linear dsDNA, ssRNA Plant virus: ssRNA Phage: linear dsDNA Fungi virus: dsRNA Algae virus: dsDNA DNA viruses When studying Adenovirus… • One piece of DNA can pair with one piece of mRNA coming from different location Split gene • Richard Roberts & Phillip Sharp shared 1993 Nobel Prize for the discovery of introns RNA viruses: (-) and (ds) Viral Morphology – Shape 病毒形态学:形状 • Symmetry 对称性 – Helical 螺旋形的 • Polyhedral 多面: Icosahedral 二十面体 • Complex 复合对称 • Enveloped • Enveloped Helical, Polyhedral, Complex Basic types of virus symmetry Tobacco mosaic virus (TMV) 烟草花叶病毒-helical capsid Adenovirus - icosahedral symmetry 腺病毒:二十面体对称 Complex symmetry 复合对称 “Colony Shape” 病毒群体形态 • Inclusion Body 包含体 – Polyhedron 多角体 • Plaque 噬菌斑: – Clear zones on plate Measurement of infective phages - Titer 效价 • • Titer 效价: – – Number of infective phages/ml pfu: plaque-forming unit 噬菌斑形成单位 Methods: • Double-layered plate 双层平板法: used widely • Single-layered plate 单层平板法 • Fast-slide method 玻片快速法 Measurement of titer 效价测定 Plaque Assay: double-layed Host Range 宿主范围 • Most: narrow host range – Polio virus 脊髓灰质炎病毒: nerve cells – Adenovirus 腺病毒: upper Respiratory Tract 上呼吸道 • None can cross eukaryotic/prokaryotic boundary • 20+ virus family infecting man Evolution of H5N1 & possible path to humans Phage T4 replication: 5 steps T4噬菌体复制的五个步骤 • • • • • • No growth Adsorption 吸附 Penetration 侵入 Replication 复制 Assembly (Maturation) 装配(成熟) Release 释放 Virus Replication Penetration of T4 Eukaryotic virus: entry by Engulfment/endocytosis 胞饮作用 Eukaryotic virus entry by fusion with host CM 膜融合 Maturation and release of virus by budding 出芽 无包膜dsRNA病毒入侵机制 • 3.3 Å Cryo-EM Structure of a Nonenveloped Virus Reveals a Priming Mechanism for Cell Entry • Cell, 141 (3), 472-482, 15 April 2010 • Xing Zhang, Lei Jin, Qin Fang, Wong H. Hui, Z. Hong Zhou Replication Strategy of dsDNA Viruses The Baltimore Classification Scheme Life cycle of bacteriophage 噬菌体生活周期 • Lytic Cycle 裂解性生活周期 • Only multiply and kill cell • Virulent phages 裂性噬菌体, e.g. T4 • Lysogenic Cycle 溶源性生活周期 • Either multiply via the lytic cycle or enter a quiescent state • Temperate phages 温和性噬菌体, e.g. λ Lytic Phage Multiplication Cycle 裂解性生活周期 Lysogenic Cycle 溶源性生活周期 • Integration 整合 – “Latent” – Prophage 前噬菌体: • Release – Lysogenic/phage conversion 溶源转变 Termination of Lysogeny溶源终止 Retro Viruses 反转录病毒 • Many Cancer-causing viruses • HIV – AIDS: Acquired Immunodeficiency Syndrome • Central Dogma DNA -----> mRNA ----> Protein • Retro Virus RNA --> DNA-->mRNA--> Protein How HIV attach cells? 华人科学家何大一首创“鸡尾酒疗法” • • • • • HIV逆转录酶抑制剂 HIV蛋白酶抑制剂 免疫机能调节剂 抗感染 营养支持 Vaccine for HIV ? • HIV mutates too rapidly – Reverse Transcriptase 反转录酶: at least 1 mutation each time • Asymptomatic 无症状: 1 million variants • Advanced: 100 million variants Merck AIDS Failure Hurts Global HIV Vaccine Research - Merck's HIV vaccine steps out of development • Science, 2007, Sep. 18 • Merck & Co. has stopped the Phase II trial of its V520 HIV vaccine after interim results showed that the vaccine was not effective and did not prevent infection. Viral Disease Treatment/Prevention • • No viral disease has ever been CURED by medical treatment. Viruses are not susceptible to ANTIBIOTICS Smallpox vaccine targeted to cancer?天花疫苗瞄准癌症 肝脏肿瘤用转基因病毒治疗前(上)及治疗4周后(下) • 《临床研究》: 2007-11-2 2009年12月4日《科学》:有望针对丙型肝炎的新型抗病毒药 Subvirus 亚病毒 • • • Viroid 类病毒 – – – Circular RNA without protein wrapping Smallest molecular organism Potato spindle tuber disease (PSTD) Virusoids (viroid-like) 类类病毒 – – Wrapped in plant virus (e.g. tobacco) ssRNA Prion 朊病毒 (protein infection) Viroid-infected plants can be symptomless or develop symptoms that range from mild to lethal, depending on the viroid Virus and Application • Industrial/Economic: 工业 • Medical 医学 • Recombinant DNA vectors 重组DNA – Bacteriophage and fermentation – Insect virus and biocontrol – Phage typing (e.g. Staphylococcus) Key Words • • • • • • • • • • • • Viron 病毒粒子 Capsid 衣壳 Envelope 包膜 Nucleocapsid核衣壳 Inclusion body包含体 Plaque 噬菌斑 Lytic Cycle Virulent phages 烈性噬菌体 Lysogenic cycle Temperate phages温和噬菌体 Titer 效价 Pfu 噬斑形成单位