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Chair of Microbiology, Virology, and Immunology MORPHOLOGY AND PHYSIOLOGY OF VIRUSES Welcome to Vira Kingdom! Virus: a noncellular small obligate intracellular parasites (genetic element) contains either a RNA or DNA genome surrounded by a protective, virus-coded protein coat has no its own biosynthetic machinery for energy generation and protein synthesis For propagation virus depends on specialized host cells infects a cell for its own replication, it has an extracellular state. Virus: A virus particle containing nucleic acid surrounded by protein and other macromolecular components is called virion. Viruses have a heavy dependence on host-cell structural and metabolic components. Viruses can confer important new properties on their host cell. Viruses may be non productive, latent, oncogenic, chronic or lytic. The main purpose of a virus is to deliver its genome into the host cell to allow its expression (transcription and translation) by the host cell. Some viruses infected human body Viruses How Viruses are classified Main criteria presently used are: Acid type: RNA or DNA; single-stranded or double-stranded; strategy of replication. Size and morphology, including type of symmetry, number of capsomeres, and presence of membranes. Presence of specific enzymes, particularly RNA and DNA polymerases, and neuraminidase Susceptibility to physical and chemical agents, especially ether. Immunologic properties. Natural methods of transmission. Host, tissue, and cell tropisms. Pathology; inclusion body formation. Symptomatology. Classification of Viruses By genome structure (DNA or RNA, single or double stranded, particle structure, presence or absence of envelope, chemical and immunological properties - most widely used) By symptomatology - oldest By routes of transmission Plant, animal or bacterial Classification by Symptomatology Dermatotropic - lesions of skin and mucous membranes cold sores, shingles, warts Pneumotropic flue, parainfluenza, respiratory syncytial viral pneumonia, Neurotropic - CNS encephalitis, Viscerotropic others? - organs hepatitis, infectious parotitis Generalized Classification According to Routes of Transmission Respiratory transmission Influenza A virus Faecal-oral transmission Enterovirus Blood-borne transmission Hepatitis B virus Sexual Transmission HIV Animal or insect vectors Rabies virus, Western equine encephalitis, yellow fever, West Nile fever, dengue fever Classification according to Biologic, Chemical, and Physical Properties DNA-Containing Viruses RNA-Containing Hepadnaviridae Viruses Picornaviridae Paramyxoviruses Parvoviridae Caliciviridae Orthomyxoviruses Papovaviridae Togaviruses Bunyaviridae Adenoviridae Flaviviridae Arenaviridae Herpesviridae Coronaviridae Reoviridae Poxviridae Rhabdoviridae Birnaviridae Iridovoridae Filoviridae Retroviridae Classification of viruses Viral morphological types Structure of viruses There are two major structures of viruses called the naked nucleocapsid virus (left) and the enveloped virus (right) CAPSID FUNCTIONS PACKAGING OR CONDENSATION OF NUCLEIC ACID PROTECTION OF NUCLEIC ACID TRANSPORT NUCLEIC ACID FROM CELL TO CELL PROVIDES SPECIFICITY FOR ATTACHMENT Virus Specific Enzymes Some viruses have enzymes for Penetration of the host cell ex. Haemagglutinin, Neuraminidase, bacteriophages have Lysozyme for penetration of bacterial cell walls Replication of viral nucleic acid ex. Retroviruses carry Reverse transcriptase Viral structure Definitions: Virion - physical particle of the virus Core - nucleic acid and tightly associated proteins within the virion Capsid - protein shell around NA or core Capsomere - protein subunit making up the capsid Nucleocapsid - core and capsid Envelope - lipid membrane found on some viruses, often derived by budding from infected cells. Peplomer - ("spike”) - morphological unit projecting from the envelope or surface of a naked virion VIRUS STRUCTURE Capsid symmetry Helical Complex Icosahedral Helical Capsid In the replication of viruses with helical symmetry, identical protein subunits (protomers) selfassemble into a helical array surrounding the nucleic acid, which follows a similar spiral path. Such nucleocapsids form rigid, highly elongated rods or flexible filaments This category includes many of the best known human pathogens, e.g. influenza virus, mumps & measles viruses, & Rabies virus Tobacco mosaic diseases virus ICOSAHEDRAL CAPSID A polyhedron with 20 equilateral faces and 12 vertices capsomers ring or knob-shaped units made of 5 or 6 protomers pentamers (pentons) – 5 subunit capsomers hexamers (hexons) – 6 subunit capsomers VIRUSES WITH CAPSIDS OF COMPLEX SYMMETRY many viruses do not fit into helical or icosahedral symmetry Examples: poxviruses and large bacteriophages Vaccinia virus T4 phage Binal symetry: head icosahedron, tail helical. Tail fibers and sheath used for binding and pins for injecting genome 200x400x250 nm, enveloped virus DNA With double membrane envelope. Examples of medically important DNA viruses. Examples of medically important RNA viruses. Chemical composition of viruses Nucleic acids (1-40 %) Proteins Lipids Glycolipids Glycoproteins Viral proteins (70-90 %): structural (capside, envelope, matrix, core, associated with nucleic acid) non-structural Structural proteins are in virion in its extracellular state. Functions: protection of nucleic acid, interaction with the membrane of susceptible cell provide viral penetration into the cell, have RNA- and DNA-polymerase activity etc. Non-structural proteins are absent in virion in its extracellular state, but they are formed during viral reproduction Functions: provide regulation of viral genome expression, are viral precursor proteins and can inhibit cell biosynthesis. Lipids (15-35 %) are in enveloped viruses in their envelope Functions: Stabilization of viral shell, Protection of inner virion shells and nucleic acid, Deproteinization of virions Carbohydrates molecules are in glycoproteins and glycolipids (3,5-9 %). They protect these molecules from cell proteases action Viral reproduction Feature: disjunctive way of reproduction Synthesis of viral genome and viral proteins is interrupted in the space and in the time: Nucleic acids are synthesized in the cell nucleus and proteins – in the cytoplasm Note: Each virus requires different strategy depending on its nucleic acid DNA viruses often enter the nucleus RNA viruses typically replicate in cytoplasm Must consider: What serves as template for replication and how mRNA is transcribed adsorption penetration uncoating synthesis Transcription of viral genes DNA replication maturation Assembly Replication of viruses budding Translation Proteins Attachment of viruses Chemical attraction Animal viruses do not have tails or tail fibers Have glycoprotein spikes or other attachment molecules that mediate attachment Penetration Penetration of animal viruses occur by direct penetration (a), fusion (b) between the viral envelope and the the host cell membrane or endocytosis (c) clathrin-coated pits Uncoating and synthesis of viruses rely on the host’s metabolic systems. Types of Viral Genomes and Their Replication Two events critical to viral infection: The production of virus structural proteins and enzymes Replication of the viral genome (dsDNA, ssDNA, dsRNA, ssRNA) dsDNA Viruses Contain dsDNA genome Most dsDNA viruses replicate their genomes in the nucleus of the cell Use host’s DNA and RNA synthesizing machinery Adapted from D. R. Harper. Molecular Virology, Second Edition. BIOS Scientific Publishers, 1999. ssDNA Viruses Contain ssDNA genomes Adapted from D. R. Harper. Molecular Virology, Second Edition. BIOS Scientific Publishers, 1999. ss/dsDNA Viruses (Using an RNA intermediate) Virus carries it’s own reverse transcriptase dsDNA enters the nucleus, forms an episome Virus does not encode an integrase gene dsRNA viruses Contain dsRNA segmented genomes Viral polymerase Adapted from D. R. Harper. Molecular Virology, Second Edition. BIOS Scientific Publishers, 1999. +ssRNA Viruses Contain +ssRNA nonsegmented genomes The RNA in the virus particle functions as mRNA Viral mRNA is recognized by cellular translational machinery Contain a viral RNAdependent RNA polymerase in order to replicate viral genomes Adapted from D. R. Harper. Molecular Virology, Second Edition. BIOS Scientific Publishers, 1999. -ssRNA viruses Contain -ssRNA segmented or nonsegmented genomes Contain a viral RNA-dependent RNA polymerase gene Adapted from D. R. Harper. Molecular Virology, Second Edition. BIOS Scientific Publishers, 1999. Viruses with ssRNA Genomes That Use a dsDNA Intermediate to Replicate Unique biology Viral genome is reverse transcribed and integrated as a cDNA into the host’s chromosome Assembly All of the components of the virus assembled into a particle Occurs when an appropriate concentration of virus proteins and genomic nucleic acids are reached and localized at specific sites within the infected cell Some particles self-assemble Viral release from cell Cell lysis, “burst” Simple viruses Budding Enveloped viruses > 4000 (poxviruses) - >100 000 (polyoviruse) Types of viral infection Productive Аbortive Virogeny Viruses caused the virogeny are temperately ones Measuring the Size of Viruses Filtration Through Membranes of Graded Porosity: Sedimentation Ultracentrifuge in the Direct Observation in the Electron Microscope: Ionizing Radiation: Comparative Measurements: Staphylococcus has a diameter of about 1000 nm; Bacteriophages vary in size (10-100 nm). Representative protein molecules range in diameter from serum albumin (5 nm) and globulin (7 nm) to certain hemocyanins (23 nm). Cultivation of viruses Laboratory animals Chick embryos Tissues cultures Bacteria (for bacteriophages) The early developing bird embryo contains a protective case, providing an ideal environment for viral propagation. POCKS on Chorio-Allantoic Membrane of Chick Embryo: Vaccinia virus (left) HSV-1 (right) 1949 - Enders, Weller, & Robinson - grow polio in non-neural cells Cells can grow as monolayers or in suspension cultures: glass (in vitro) and plastic Types of cell culture Primary Diploid Continuous Tissue Culture Primary cell lines are derived directly from tissue after treatment with trypsin. Die after a few generations - Limited to 5-20 cell divisions Fibroblasts of human embryo, Rhesus monkey kidney, Chiken fibroblasts Continuous cell lines - immortal cells derived from tumors or mutagenesis of primary cells. HeLa (Henrietta Lacks), HEp-2 (Hu. Epithelial), BHK (Baby Hamster Kidney), Detroit-6. Disadvantages: May not resemble the original cell of origin Less differentiated - lost morphological and biochemical features Can be tumorigenic Diploid cell lines - homogeneous population of a single type (fibroblastliked cell). Typically derived from tumors. Can divide up to 100 times. Remain diploid WI-38, MRC-5, MRC-9, IMR-90 Morphologic and Structural Effects Cytocidal effect, or necrosis of cells Normal cells Hemadsorption Formation of syncytia, or polykaryocytes Giant multynucleated skin cells (simple herpes virus) Infected cells Morphologic and Structural Effects Inclusion Body Formation granules in cytoplasm and/or nucleus of infected cells Large cells with typical nuclear “owl’s eye” inclusions Cell rounding Morphologic transformation by an oncogenic virus Normal cells Infected cells Cell culture obtaining Inoculation of laboratory animal Intracerebrally Intraperitoneally Intramuscularly Intravenously Intranasally Bacteriophage Bacterial virus Multiplication is similar to animal viruses except for the penetration (inject DNA), release (lyses) and prophage (lysogeny) stages T-even bacteriophage penetrate the host cell by specifically binding and injecting their DNA into the host cell After viral multiplication inside the host cell, viral enzymes will weaken the host cell membrane, rupture the cell (lyses), and release numerous virions A weakened bacterial cell, crowed with viruses. Prions (Proteinaceous infectious particles) Protein particle with no nucleic acid, no envelope, no capsid The nature of these agents is still controversial Presently thought to be unusual proteins lacking nucleic acid and more resistant to proteases than normal proteins They resist inactivation by UV, ionizing radiation, formaldehyde and heat Have amino acid sequence identical to normal brain protein, PrPc, (gene on chromosome 20) but folded differently (designated PrPs) Current theory is that prion protein enters brain tissue and binds to normal pre-prion protein and converts it into a prion protein form They increase in number during long incubation periods Much smaller that the smallest virus In 1997 Dr. Stanley Prusiner received a Nobel Prize for work on these agents Hypothesis of how a protein can be infectious Prions Spongiform encephalopathies slow neurological diseases, fatal spongelike appearance of brain tissue as neurons degenerate main signs are dementia and unsteadiness Animal diseases BSE - bovine spongiform encephalopathy i.e. mad cow disease chronic wasting disease (in mules, deer, elk) mink encepahlopathy scrapie in sheep Human Prion Diseases Kuru Creutzfeldt-Jakob disease (CJD) Gerstmann-Straussler-Scheinker disease (GSS) Fatal familial insomnia (FFI) Kuru (means shivering or trembling) Disease limited to the Fore tribe of New Guinea who practiced cannibalism Congestion of blood vessels. Degeneration of cerebral cortex in long term cases Observe vacuoles or holes of Kuru infected brain Creutzfeldt-Jakob Disease The human variant of mad cow disease Transmission between humans is unusual injection, transplantation (e.g., corneas) Symptoms progressive dementia, muscle wasting, unsteadiness Possible genetic link because the disease runs in families Viroids Much smaller than viruses Single stranded RNA, no capsid 300-400 nucleotides 1/10 the size of the smallest infectious viral RNA Cause plant diseases potato spindle tuber (PSTV) chrysanthemum stunt cucumber pale fruit Hopstunt Tomatoes pathogens Potato Spindle Tuber Viroid (PSTV)