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An Introduction to the Viruses Chapter 6 The Search for the Elusive Virus • ______________ 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 evolution of Bacteria, Archaea, and Eukarya • Viruses are obligate intracellular parasites 3 3 Size of viruses Naming viruses Classified based on structures, size, nucleic acids, host species, target cells. • 3 orders, 63 families, and 263 genera of viruses • Family name ends in -viridae • Genus name ends in -virus, Simplexvirus, Hantavirus, Enterovirus • Name of genus or family begins with description of virus – – – – appearance: togavirus, coronavirus place collected: adenovirus, hantavirus effect on host: lentivirus acronymns: picornavirus; (arbovirus) 7 7 Examples • Family – Herpesviridae • Genus – Varicellovirus • Common name – chickenpox virus • Disease - chickenpox • Family – Herpesviridae • Genus – Simplexvirus • Common name – herpes virus (Herpes simplex virus I (HSV-I) • Disease – fever blisters, cold sores terminology • Virus = virus particle • ___________– fully formed, virulent, extracellular • ___________– host cell is lysed (broken) to release virions • ___________– viruses are inactive (latent stage) and host cell isn’t lysed (virus may be integrated within host genome) 9 Viral structure • ___________ (with spikes/receptors; 13/20 – derived from host cell) – may not be present • ___________ (morphologies: helical, icosohedral, complex) • Nucleic acid (DNA/RNA; ds or ss) • Matrix proteins (some enzymes) 10 11 capsids • Nearly all viruses have capsids- protein coats that enclose & protect their nucleic acid • Each capsid is constructed from identical subunits called capsomers made of protein – can self-assemble • ___________= capsid & nucleic acid • 2 types (based on shape): – helical – icosahedral Envelope • If present, made primarily of lipids • ______________________ ; (ER, nuclear envelope, cell membrane-budding) • May be embedded with spikes for host recognition/binding 13 4 morphological types • Due to capsule shape and/or whether it’s enveloped 1. Helical 2. Icosahedral 3. Enveloped (with Hel. or Icos. capsid) 4. complex 14 Morphological types 1. Helical capsid • Rod-shaped • • capsomers Coil around hollow center Nucleic acid is kept inside – wound-up within tube (nucleocapsid) 15 Morphological types Helical – capsid surrounds DNA like hollow tube Ex: TMV, influenza, measles, rabies (last 3 are enveloped) Morphological types Tobacco Mosiac Virus Influenza virus 17 Morphological types 2. icosahedral • 20-sided with 12 • • • corners Vary in the number of capsomers Each capsomer may be made of 1 or several proteins Some are enveloped Figure 6.7 Figure 6.8 19 19 Morphological types Human papilloma virus Adenovirus Icosahedral – 3D, 20 sided Herpesvirus Morphological types 3. envelope • Naked viruses – Capsid proteins exposed to environment – Released from cells as cells ____________________ – Not a good pathogenic feature should keep host alive • Enveloped viruses – Covered with a lipid bilayer – ______________________ – Host cell keeps producing virus much longer sometimes for extended periods – Can bud off cell – thereby not destroying (lysing) it 21 Morphological types Enveloped vs. naked viruses 22 Morphological types 4. Complex viruses • Have additional or special structures • Examples: • ___________– lack normal capsid – instead, layers of lipoprotiens and fibrils on surface • ___________viruses have a polyhedral head, helical tail and fibers for attachment. 23 Morphological types Fig 6.9a,c 25 Nucleic Acids • 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 26 26 Nucleic Acids • 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 27 27 Enzymes important to replication • Pre-formed enzymes may be present – ___________– DNA or RNA – ___________– copy RNA – ______________________– synthesis of DNA from RNA (AIDS virus) 28 28 Viral life cycles 29 Life cycle Host range • Spectrum of cells a virus can infect – cell has to have a specific structure (receptor) on its surface for viral attachment – cell has to contain all of the enzymes and materials needed to produce new virions • May be one species or many – HIV (only humans) vs rabies (many animals) – Bacteriophages – tend to be very specific • May be one tissue or many within a host – Hepatitis (liver) vs polio (intestinal & nerve cells) DNA replication in viruses * Uses host machinery!* 31 animal virus replication (life cycle) Viral Multiplication – animal viruses 1. ___________– binding of virus to specific molecule on host cell 2. ___________– genome enters host cell 3. ___________– the viral nucleic acid is released from the capsid 4. ___________– viral components are produced 5. ___________– new viral particles are constructed 6. ___________– assembled viruses are released by budding (exocytosis) or cell lysis 33 34 34 1. Adsorption and Host Range • Virus coincidentally collides with a susceptible host cell and adsorbs specifically to receptor sites on the cell membrane • Spectrum of cells a virus can infect – host range – ___________– human liver cells – ___________– primate intestinal and nerve cells – ___________– various cells of many mammals 35 35 1. Adsorption to host cell membrane (a) Coronavirus with envelope spikes (b) adenovirus (naked capsid) with surface capsid spikes 36 36 Entry: (2. penetration & 3. uncoating) Entry (viruses with envelopes) • first must attach to cell membrane using receptors -usually specific for host AND cell type • After adsorption _________ of membranes – (like two soap bubbles) • leaves the capsid free in the cytoplasm Entry (viruses without envelopes) • first must attach using receptors (specific) • if a match, then engulfment -- ___________ • capsid then in the cytoplasm but within a vacuole • virus must uncoat without the genes being degraded 37 Figure 6.13 Entry of viruses into cells (penetration and uncoating) • Endocytosis and engulfment of herpesvirus; • Fusion of cell membrane with viral envelope (mumps) 38 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 ___________ • RNA viruses generally are replicated and assembled in the ___________ – Positive-sense RNA contain the message for translation – Negative-sense RNA must be converted into positive-sense message 39 39 Duplication and synthesis: viral replication (more details in Ch. 9) Transport of DNA/RNA to nucleus • most viruses must get genes to nucleus to survive • some integrate into host DNA (leads to latency) – may require conversion of RNA copy to DNA • some remain independent chromosomes Viral replication • some do direct copies of DNA->DNA or RNA->RNA • others use "reverse transcriptase" to do RNA->DNA conversion – then DNA->RNA using HOST enzymes – timing is important -- some replicate only late in the cycle, after all proteins are made 40 5. Assembly: Filling the capsid • Capsid proteins made in cytoplasm • DNA or RNA gets fills empty capsids • final modifications to capsid – to plug any holes from DNA/RNA entry – to mature the outer proteins 41 6. Release • Two ways assembled viruses leave host cell: 1. ___________– exocytosis; nucleocapsid binds to membrane which pinches off and sheds the viruses gradually; cell is not immediately destroyed 2. ___________– nonenveloped and complex viruses released when cell dies and ruptures • Number of viruses released is variable – 3,000-4,000 released by poxvirus – >100,000 released by poliovirus 42 42 Viral budding – picking up cell membrane upon exit Budding of parainfluenza virus Budding of HIV 43 Damage to Host Cell Cytopathic effects - virus-induced 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 44 44 Figure 6.16 45 45 46 46 Persistent infections with viruses • Persistent infections - cell harbors the virus and is not immediately lysed • Can last weeks or host’s lifetime; several can periodically reactivate – ______________________ – 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 47 47 Persistent infections with viruses • Some animal viruses permanently alter genetic material ________________ • Transformed cells have increased rate of growth, altered chromosomes, and can become “immortal” tumors (cancerous or noncancerous growths) • Mammalian viruses capable of initiating tumors are called _________________ – Papillomavirus – genital warts/cervical cancer – Epstein-Barr virus – Burkitt’s lymphoma – HBV and liver cancer 48 Multiplication Cycle in 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 49 6 Steps in Phage Replication 1. Adsorption – binding of virus to specific 2. 3. 4. 5. 6. molecule on host cell Penetration – genome enters host cell Replication – viral components produced Assembly – viral components assembled Maturation – completion of viral formation Release – viruses leave cell to infect other cells 50 Figure 6.17 51 51 Figure 6.18 Figure 6.19 52 52 Lysogeny: The Silent Virus Infection • Not all phages complete the lytic cycle • Some DNA phages (temperate phages), undergo • • • adsorption and penetration but don’t replicate The viral genome inserts into bacterial genome and becomes an inactive ___________– the cell is not lysed Prophage is retained and copied during normal cell division transfer of temperate phage genome to all host cell progeny – ___________ Induction can occur resulting in activation of lysogenic prophage followed by viral replication and cell lysis 53 53 Figure 6.17 54 54 Lysogeny • Lysogeny results in the spread of the virus without ______________________ • Phage genes in the bacterial chromosome can cause the production of toxins or enzymes that cause pathology – lysogenic conversion – Corynebacterium diphtheriae – Vibrio cholerae – Clostridium botulinum 55 55 56 56 Growing animal viruses Viral Culture Obligate intracellular parasites that require appropriate cells to replicate 1. live animals (dependent on host specificity) 2. bird embryos – chicken, duck; intact, self-supporting unit, sterile, selfnourished 3. cell culture – can be used to cultivate but also to test toxic (ex. Hemolytic) effects Figure 6.20 58 Figure 6.21 59 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 60 Detection of Animal Viral Infections • More difficult than other agents • Consider overall clinical picture • Take appropriate sample – Infect cell culture – look for characteristic cytopathic effects – Screen for parts of the virus – Screen for immune response to virus (antibodies) 61 diagnosis Treatment of viral infections • Antiviral drugs • Target viral replication – but usually lots of side effects (affects host cells too) • Some drugs target virus-specific enzymes Best bet…get ___________and avoid infection 63 Clinically-important viruses (just a few examples!) HepC 64 Important viruses you should know… • Smallpox (variola major, minor) – complex virus; inclusions • Herpesviridae – (herpes; chicken pox – varicella zoster); • • • • • • • • • chronic latent state reactivated; nuclear inclusions HPV – can transform cells; warts cervical cancer Hepatovirus (A, B, C) – see table Polio – enterovirus – enteric (oral vaccine) Cold (Rhinovirus) – antibiotics ineffective! It’s a virus!! West Nile – is a flavivirus; spread by moquitoes; bird is reservoir SARS – coronavirus (like the virus that causes bronchitis); prominent spikes on envelope influenza – Flu; Type A is the one you’ve had; Rotavirus – viral food poisoning; vomiting and diarrhea – sometimes concurrently!! HIV – retrovirus; latency; (see slide) 65 Herpesviridae • Examples: – _______________ (cold sores); 2 (genital herpes) – ______________________ (chicken pox) • Have chronic latent phase in nerve cells • Reactivated by various stimuli: – Foods – Sunlight – Stress • Chicken pox reappears as “___________” 66 Hepatoviruses and Hepatitis Organism Hep A Hep B Hep C Virus Non-enveloped; ssRNA Enveloped; ss and dsDNA RNA (flaviviridae) Disease Short-term hepatitis Chronic infection (6%), liver cancer, death Chronic infection (7585%) liver disease very common, cancer, death Transmission Fecal/oral Blood/fluid contact (IV, sex, tattoos); vertical Blood/fluid contact (IV, sex, tattoos); vertical Treatment Immune globulin Interferon, nucleoside analogs Interferon or ribavirin Prevention Vaccine Vaccine No vaccine; avoid exposure Special notes Resolves (selflimiting); avoid aspirin, alcohol Survives in infected blood for days, freezing “silent epidemic; 4M people, 80% asymptomatic! 67 Influenza • Type A = Hong Kong, Asian, Swine flu; Avian Influenza (bird flu – emerging disease) • Bird human (right now) Pandemic: human human; antigenic shift Influenza pandemic of ________ killed 20+ million people! (more than plague?) The viruses of the last three global influenza pandemics were first found in China. 68 HIV • Retrovirus – ssRNA genome – depends on Reverse • • • • Transcriptase to make DNA (will be covered later) Latent phase – inserts in host genome – 2 wks. - 20 years? – can’t see virus particles in bloodstream Infects cells – CD4+ T-cells (lymphocytes), macrophages Destroys immune system AIDS person frequently dies from 2ndary infection and/or cancer HIV also attacks organs directly (kidney, heart) 2007 data: • number of people living with HIV = ___________ • Number of people who died of AIDS = __________ 69 HIV – enveloped virus • HIV does not survive well outside the human body or in the outside the environment. (Enveloped – fragile – does not survive drying) • The studies also shown that drying HIV reduces the amount of viral by nearly 95 percent within several hours. 70 HIV/AIDS – stages • Stage I: asymptomatic, not categorized as AIDS • Stage II: include minor mucocutaneous manifestations • • (ex. recurrent yeast infections) and recurrent upper respiratory tract infections Stage III: includes unexplained ______________ for longer than a month, severe bacterial infections and pulmonary tuberculosis. Wasting begins. Stage IV includes ___________of the brain, candidiasis of the esophagus or repiratory, Pnemocystis carinii pneumonia, and Kaposi's sarcoma (cancer); these diseases are used as indicators of AIDS. 71 Other noncellular infectious particles ___________- misfolded proteins, contain no nucleic acid – Cause transmissible spongiform encephalopathies – fatal neurodegenerative 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) – Extremely resistant to usual sterilization techniques 72 72 Figure 6.22 73 73 Other Noncellular Infectious Agents • Satellite viruses – dependent on other viruses for replication – Adeno-associated virus – replicates only in cells infected with adenovirus – Delta agent – naked strand of RNA expressed only in the presence of hepatitis B virus • ___________ – short pieces of RNA, no protein coat; only been identified in plants 74 74