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Chapter 6 An Introduction to Viruses Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 6.1 Overview of Viruses • Louis Pasteur postulated that rabies was caused by a virus (1884) • Ivanovski and Beijerinck showed a disease in tobacco was caused by a virus (1890s) • 1950s virology was a multifaceted discipline – Viruses: noncellular particles with a definite size, shape, and chemical composition 2 The Position of Viruses in the Biological Spectrum • There is no universal agreement on how and when viruses originated • Viruses are considered the most abundant microbes on earth • Viruses played a role in the evolution of Bacteria, Archaea, and Eukarya • Viruses are obligate intracellular parasites 3 6.2 The General Structure of Viruses • Size range – most <0.2 μm; requires electron microscope Figure 6.1 Size comparisons BACTERIAL CELLS Rickettsia 0.3 mm Viruses 1. Poxvirus 2. Herpes simplex 3. Rabies 4. HIV 5. Influenza 6. Adenovirus 7. T2 bacteriophage 8. Poliomyelitis 9. Yellow fever Streptococcus 1 mm (1) (2) Protein Molecule 10. Hemoglobin molecule 250 nm 150 nm 125 nm 110 nm 100 nm 75 nm 65 nm 30 nm 22 nm E. coli 2 mm long (10) (9) (8) 15 nm (7) (3) (6) (4) (5) 4 YEAST CELL – 7 mm Viral Components: Capsids, Nucleic Acids, and Envelopes • Viruses bear no resemblance to cells – Lack protein-synthesizing machinery • Viruses contain only the parts needed to invade and control a host cell Capsid Covering Envelope (not found in all viruses) Virus particle Nucleic acid molecule(s) (DNA or RNA) Central core Matrix proteins Enzymes (not found in all viruses) 5 The Generalized Structure of a Virus • Capsids – All viruses have capsids (protein coats that enclose and protect their nucleic acid) – The capsid together with the nucleic acid is the nucleocapsid – Some viruses have an external covering called an envelope; those lacking an envelope are naked – Each capsid is made of identical protein subunits called capsomers Figure 6.4 Capsid Nucleic acid (a) Naked Nucleocapsid Virus Envelope Spike Capsid Nucleic acid 6 (b) Enveloped Virus The Viral Capsid: The Protective Outer Shell • Two structural capsid types: – Helical continuous helix of capsomers forming a cylindrical nucleocapsid – Icosahedral Discs Nucleic acid Capsomers (a) (b) Nucleic acid Capsid begins forming helix. Figure 6.5 Assembly of helical nucleocapsids (c) 7 General Structure of Viruses • Two structural capsid types: – Helical – Icosahedral: 20-sided with 12 corners (a) Capsomers Facet Capsomers Vertex Nucleic acid (b) Capsomers Vertex Fiber (c) Figure 6.7 Structure and formation of an icosahedral virus 8 (d) © Dr. Linda Stannard, UCT/Photo Researchers, Inc. Figure 6.6 General Structure of Viruses • Viral envelope – Mostly animal viruses – Acquired when the virus leaves the host cell – Exposed proteins on the outside of the envelope, called spikes, are essential for attachment of the virus to the host cell Capsid Nucleocapsid Nucleic acid © Dennis Kunkel/CNRI/Phototake (b) (a) Hemagglutinin spike Neuraminidase spike Matrix protein Lipid bilayer Nucleocapsid (c) 50 nm Spikes Nucleocapsid 9 (d) Dr. F. A. Murphy/CDC Functions of Capsid/Envelope • Protects the nucleic acid when the virus is outside of the host cell • Helps the virus bind to a cell surface and assists the penetration of the viral DNA or RNA into a suitable host cell Capsomers © Dr. Linda Stannard, UCT/Photo Researchers, Inc. Fred P. Williams, Jr./EPA (a) Envelope Capsid DNA core Figure 6.8 Two types of icosahedral viruses, highly magnified 10 (b) © Eye of Science/Photo Researchers, Inc. Complex Viruses: Atypical Viruses • Complex viruses: atypical viruses – Poxviruses lack a typical capsid and are covered by a dense layer of lipoproteins – Some bacteriophages have a polyhedral nucleocapsid along with a helical tail and attachment fibers 240 – 300 nm a. a poxvirus Nucleic acid Core membrane Nucleic acid (a) Capsid head Collar 200 nm Outer envelope Soluble protein antigens Sheath Lateral body Tail fibers Tail pins b./c. bacteriophages Base plate (c) Figure 6.9 Complex viruses (b) © Bin Ni, Chisholm Lab, MIT 11 Figure 6.10 Types of Viruses A. Complex Viruses B. Enveloped Viruses Helical Icosahedral (1) (3) (5) (2) (4) (6) C. Nonenveloped Naked Viruses Helical Icosahedral (8) (7) (9) A. Complex viruses: (1) poxvirus, a large DNA virus (2) flexible-tailed bacteriophage B. Enveloped viruses: With a helical nucleocapsid: (3) mumps virus (4) rhabdovirus With an icosahedral nucleocapsid: (5) herpesvirus (6) HIV (AIDS) C. Naked viruses: Helical capsid: (7) plum poxvirus Icosahedral capsid: (8) poliovirus (9) papillomavirus 12 Nucleic Acids: At the Core of a Virus • Viral genome – either DNA or RNA but never both • Carries genes necessary to invade host cell and redirect cell’s activity to make new viruses • Number of genes varies for each type of virus – few to hundreds 13 Nucleic Acids: At the Core of a Virus • DNA viruses – Usually double stranded (ds) but may be single stranded (ss) – Circular or linear • RNA viruses – Usually single stranded, may be double stranded, may be segmented into separate RNA pieces – ssRNA genomes ready for immediate translation are positive-sense RNA – ssRNA genomes that must be converted into proper form are negative-sense RNA 14 General Structure • Pre-formed enzymes may be present – Polymerases: DNA or RNA – Replicases: copy RNA – Reverse transcriptase: synthesis of DNA from RNA (AIDS virus) 15 6.3 How Viruses Are Classified and Named • Main criteria presently used are structure, chemical composition, and genetic makeup • Currently recognized: 3 orders, 63 families, and 263 genera of viruses • Family name ends in -viridae, i.e.Herpesviridae • Genus name ends in -virus, Simplexvirus • Herpes simplex virus I (HSV-I) 16 Human Viruses & Viral Diseases 17 18 6.4 Modes of Viral Multiplication General phases in animal virus multiplication cycle: 1. Adsorption – binding of virus to specific molecules on the host cell 2. Penetration – genome enters the host cell 3. Uncoating – the viral nucleic acid is released from the capsid 4. Synthesis – viral components are produced 5. Assembly – new viral particles are constructed 6. Release – assembled viruses are released by budding (exocytosis) or cell lysis 19 Figure 6.11 Animal Virus Multiplication Penetration. The virus is engulfed into a vesicle and its envelope is Uncoated, thereby freeing the viral RNA into the cell cytoplasm. Synthesis: Replication and Protein Production. Under the control of viral genes, the cell synthesizes the basic components of new viruses: RNA molecules, capsomers, spikes. Assembly. Viral spike proteins are inserted into the cell membrane for the viral envelope; nucleocapsid is formed from RNA and capsomers. Release. Enveloped viruses bud off of the membrane, carrying away an envelope with the spikes. This complete virus or virion is ready to infect another cell. 20 Adsorption and Host Range • Virus coincidentally collides with a susceptible host cell and adsorbs specifically to receptor sites on the membrane • Spectrum of cells a virus can infect – host range – Hepatitis B: human liver cells – Poliovirus: primate intestinal and nerve cells – Rabies: various cells of many mammals Figure 6.12 Envelope spike Host cell membrane Capsid spike Receptor Host cell membrane Receptor 21 (a) (b) Penetration/Uncoating of Animal Viruses • Flexible cell membrane is penetrated by the whole virus or its nucleic acid by: – Endocytosis: entire virus is engulfed and enclosed in a vacuole or vesicle – Fusion: envelope merges directly with membrane resulting in nucleocapsid’s entry into cytoplasm 22 Synthesis: Replication and Protein Production • Varies depending on whether the virus is a DNA or RNA virus • DNA viruses generally are replicated and assembled in the nucleus • RNA viruses generally are replicated and assembled in the cytoplasm – Positive-sense (+) RNA contain the message for translation – Negative-sense (-) RNA must be converted into positive-sense message 23 Release of Mature Viruses • Assembled viruses leave the host cell in one of two ways: – Budding: exocytosis; nucleocapsid binds to membrane which pinches off and sheds the viruses gradually; cell is not immediately destroyed – Lysis: nonenveloped and complex viruses released when cell dies and ruptures Host cell membrane (b) © Chris Bjornberg/Photo Researchers, Inc. Figure 6.14 Maturation and release of enveloped viruses Viral nucleocapsid Viral glycoprotein spikes Cytoplasm Capsid RNA Budding virion (a) Viral matrix protein Free infectious virion with envelope 24 Damage to the Host Cell and Persistent Infections Cytopathic effects - virusinduced damage to cells 1. Changes in size and shape 2. Cytoplasmic inclusion bodies 3. Inclusion bodies 4. Cells fuse to form multinucleated cells 5. Cell lysis 6. Alter DNA 7. Transform cells into cancerous cells Multiple nuclei Normal cell Giant cell CDC (a) CDC Inclusion bodies Figure 6.15 Cytopathic changes in cells 25 (b) © Massimo Battaglia, INeMM CNR, Rome Italy Persistent Infections • Persistent infections - cell harbors the virus and is not immediately lysed • Can last weeks or host’s lifetime; several can periodically reactivate – chronic latent state – Measles virus – may remain hidden in brain cells for many years – Herpes simplex virus – cold sores and genital herpes – Herpes zoster virus – chickenpox and shingles 26 Viral Damage • Some animal viruses enter the host cell and permanently alter its genetic material resulting in cancer – transformation of the cell • Transformed cells have an increased rate of growth, alterations in chromosomes, and the capacity to divide for indefinite time periods resulting in tumors • Mammalian viruses capable of initiating tumors are called oncoviruses – Papillomavirus: cervical cancer – Epstein-Barr virus: Burkitt’s lymphoma 27 6.5 The Multiplication Cycle in Bacteriophages • Bacteriophages – bacterial viruses (phages) • Most widely studied are those that infect Escherichia coli – complex structure, DNA • Multiplication goes through similar stages as animal viruses • Only the nucleic acid enters the cytoplasm uncoating is not necessary • Release is a result of cell lysis induced by viral enzymes and accumulation of viruses lytic cycle 28 Steps in Phage Replication 1. Adsorption – binding of virus to specific molecules on host cell 2. Penetration – genome enters host cell 3. Replication – viral components are produced 4. Assembly – viral components are assembled 5. Maturation – completion of viral formation 6. Lysis & Release – viruses leave the cell to infect other cells 29 Figure 6.16 Multiplication of Bacteriophage E. coli host 7 Release of viruses Bacteriophage Bacterial DNA Lysogenic State Viral DNA 1 2 Viral DNA becomes latent as prophage. Adsorption 6 Penetration Lysis of weakened cell Lytic Cycle DNA splits Spliced viral genome 3 Viral DNA 5 Duplication of phage components; replication of virus genetic material Maturation Bacterial DNA molecule Capsid The lysogenic state in bacteria. The viral DNA molecule is inserted at specific sites on the bacterial chromosome. The viral DNA is duplicated along with the regular genome and can provide adaptive genes for the host bacterium. Tail 4 Assembly of new virions DNA + Tail fibers Sheath Bacteriophage Bacteriophage assembly line. First the capsomers are synthesized by the host cell. A strand of viral nucleic acid is inserted during capsid formation. In final assembly, the prefabricated components fit together into whole parts and finally into the finished viruses. 30 Comparison of Bacteriophage and Animal Virus Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Head Bacterial cell wall Tube Viral nucleic acid Cytoplasm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 31 © K.G. Murti/Visuals Unlimited Lysogeny: The Silent Virus Infection • Not all phages complete the lytic cycle • Some DNA phages, called temperate phages, undergo adsorption and penetration but don’t replicate • The viral genome inserts into bacterial genome and becomes an inactive prophage – the cell is not lysed • Prophage is retained and copied during normal cell division resulting in the transfer of temperate phage genome to all host cell progeny – lysogeny • Induction can occur resulting in activation of lysogenic prophage followed by viral replication and cell lysis 32 Lytic and Lysogenic Lifecycles E. coli host 7 Release of viruses Bacteriophage Bacterial DNA Lysogenic State Viral DNA 1 2 Viral DNA becomes latent as prophage. Adsorption 6 Penetration Lysis of weakened cell Lytic Cycle DNA splits Spliced viral genome 3 Viral DNA 5 Duplication of phage components; replication of virus genetic material Maturation Bacterial DNA molecule Capsid The lysogenic state in bacteria. The viral DNA molecule is inserted at specific sites on the bacterial chromosome. The viral DNA is duplicated along with the regular genome and can provide adaptive genes for the host bacterium. Tail 4 Assembly of new virions DNA + Tail fibers Sheath Bacteriophage Bacteriophage assembly line. First the capsomers are synthesized by the host cell. A strand of viral nucleic acid is inserted during capsid formation. In final assembly, the prefabricated components fit together into whole parts and finally into the finished viruses. 33 Lysogeny • Lysogeny results in the spread of the virus without killing the host cell • Phage genes in the bacterial chromosome can cause the production of toxins or enzymes that cause pathology – lysogenic conversion – Corynebacterium diphtheriae: diphtheria – Vibrio cholerae: cholera – Clostridium botulinum: botulism 34 Medical Importance of Viruses • Viruses are the most common cause of acute infections • Several billion viral infections per year • Some viruses have high mortality rates • Possible connection of viruses to chronic afflictions of unknown cause • Viruses are major participants in the earth’s ecosystem 35 6.8 Prions and Other Nonviral Infectious Particles Prions - misfolded proteins, contain no nucleic acid – Extremely resistant to usual sterilization techniques – Cause transmissible spongiform encephalopathies – fatal neurodegenerative diseases 36 Prions Diseases Common in animals: • Scrapie in sheep and goats • Bovine spongiform encephalopathies (BSE), a.k.a. mad cow disease • Wasting disease in elk • Humans – Creutzfeldt-Jakob Syndrome (CJS) Figure 6.21 Brain cell Prion fibrils © James King-Holmes/Institute of Animal Health/Photo Researchers, Inc. (a) 37 Dr. Art Davis/CDC (b)