Acellular infectious agents

----- and ----- showed that a disease in tobacco was caused by a filterable virus in the 1890s.
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----- and ----- showed that a disease in tobacco was caused by a filterable virus in the 1890s.
D.M. Ivanovski and Martiby's Beijerkinck
"Filterable virus" that causes hoof & mouth disease in cattle
Friedrich Loeffler & Paul Frosch
Discovered "filterable virus" that destroyed bacteria- BACTERIOPHAGES
1915- F.W. Twork and F. d'Herelle
- These early researchers found that when fluids from host organisms passed through porcelain filters designed to trap bacteria, the filtrate remind infectious
- This proved that an infection could be caused by a fluid containing agents smaller than bacteria
Viruses are filterable infectious agents
1. Since viruses are unable to multiply independently from the host cell, they are not living things and should be called infectious molecules
2. Even though viruses do not exhibit most of the life processes of cells, they can direct them, and thus are certainly more than inert and lifeless molecules. we will use inactive.
The viral debate: two sides
1. Ubiquitous
2. Inactive particles: no metabolism, replication, motility
3. Structurally compact & economical
4. Small: nanometers
Properties of viruses
In nature & have had major impact on development of biological life
- 8% of human genome consist of viral DNA
- 10 to 20% of bacterial DNA contains viral sequences
- Viruses infect everything: bacteria, protozoa, algae, plants & animals
Viruses are ubiquitous
No metabolism, replication, or motility
- OBLIGATE INTRACELLULAR PARASITES
- Viral genome hijacks host cell's replication machinery
- Cannot be grown in pure culture- need to be grown with host cells
Viruses are inactive particles
- Viruses are genetic information -- DNA or RNA --- contained within protective protein coat
- NOT CELLS-- acellular infectious agent
Viruses are structurally compact & economical
- Most are 20- 150 nanometers
- Cannot be seen with a light microscope-- need an electron microscope & special staining
Viruses are very small
1. Host and diseases they caused older, clinically used 2. Structure 3. Chemical composition 4. Similarities in genetic makeup 5. 8 orders & 38 families end in -ViridaeClassification of viruses - ICTV keeps online databases and publishes features, classification, and nomenclature of viruses1. How sick are they? - viral diseases are usually milder in symptoms 2. What time of the year is it? - known illnesses circulating & seasonal infections 3. When in doubt: do blood work or testing 4. Treatment: - Antibiotics are prescribed for BACTERIAL infections - Supportive care is given for VIRAL infectionsIs it bacterial or viral? They cause the same stuff: sore throats, ear infections, meningitis, diarrheaCapsids, Nucleic acids & Envelopes - Viruses bear no resemblance to cells and lack any of the protein-synthesizing machinery found in cells - Viral structure is composed of regular, repeating, subunits that give rise to their crystalline appearance - The structure contains only those parts needed to invade and control a host cellStructure of viruses: viral componentsCapsid: protein shell that surrounds the nucleic acid - some are enveloped in the host membrane Protein coat made up of identical subunits called capsomeresExternal coating?Containing genetic information of DNA or RNACore?The capsid and nucleic acid togetherNucleocapsidDNA or RNA - dsDNA, ssDNA, dsRNA, and ssRNANucleic acid coreProvides protection & contains recognition sitesOuter covering- Most prominent feature of viruses - Constructed from identical protein subunits called capsomeres - Capsomeres spontaneously self-assemble into the finished capsid1. Capsid1. Helical: rod shaped capsomeres form a hollow disc 2. Icosahedral: 3D and 20 sided - Bacteriophages do not fit into either of these groups- complexTwo different types of capsids in animal viruses1. Envelope viruses 2. Naked (non-enveloped viruses)Two types of Viral envelope- optionalSurrounded by a lipid bilayer obtained from host cell - matrix protein: between nucleocapsid and envelope - structural link between envelope & capsid - leave host by BUDDING - enveloped viruses are often termed pleomorphic- variable in shapeEnveloped viruses- Viruses are more resistant to disinfectants - leave host by LYSIS or EXOCYTOSISNaked (non-enveloped virus)1. Protection: typically, naked or non-enveloped are harder to destroy with disinfectants 2. Location of recognition sites - bind to complementary chemicals on the surface of their specific hosts - spikes - phages attach by tail fibers - proteins recognized by immune system - used in vaccine developmentCapsid & or envelope:Are outer surface proteins that attach to receptor sites on host cellsSpikes:1. Polymerases- DNA and RNA 2. Reverse Transcriptase- RNA to cDNA 3. Proteases 4. rely on host cell for everything elseViruses can contain enzymes for specific operations within the host cell- Arenaviruses (hemorrhagic fever) package ribosomes - Retroviruses "borrow" tRNASome viruses "borrow" & package items from host cell1. Viral capsid & genetic material synthesis 2. regulating host cell actions 3. packaging of mature virusAt minimum, must carry genes for:- Four genes in Hepatitis B virus - Hundreds of genes in some herpesvirusesThe number of viral genes is quite small compared with that of a cell:Single stranded (ssDNA) or double stranded (dsDNA); linear or circular - ssDNA is non-existent in cells- only seen in viruses. PAMPSDNA virusesCan be double stranded, but more often single stranded: 1. Positive sense RNA 2. Negative sense RNA 3. Segmented 4. RetrovirusesRNA virusesReady for immediate translation- like mRNAPositive sense RNAMust be converted before translation can occur. Template strandNegative sense RNAIndividual genes exist on separate pieces of RNASegmentedCarry their own enzymes to create DNA out of their RNARetrovirusesTransmissible & able to establish an infectionVirion extracellular state of a fully formed virus1. Attachment 2. Entry 3. Synthesis 4. Assembly 5. ReleaseGeneral steps in a viral replicationOf virion to host cell. Called absorption for animal virusesAttachment in viral replicationOf virion or genome into host cell - penetration & uncoating of animal virusesEntry in viral replicationOf nucleic acids and viral proteins by the host cells enzymes, tRNAs, and ribosomesSynthesis in viral replicationOf new virions within the host cellAssembly in viral replicationOf new virions from the host cell - Process takes hours to days depending on virus typeRelease in viral replication- viruses bind to receptors on host cell surface, usually glycoproteins on cytoplasmic membrane. virus attaches with their SPIKE PROTEINS - often more than one host receptor is required for attachment- CD4 & CCR5 - there is normal function of the receptor molecule unrelated to viral infectionAbsorption/attachment of virion to host cell1. Host range 2. TropismTwo parts to absorption/attachment of animal viral replicationSpecies type of virus can infect - Most viruses infect a single species - Covid infects bats, swine, pangolin, civets, & miceHost rangeCell type or tissue type virus infects - virus must attach to specific receptor- location determines type of disease - ACE-2 receptors on epithelial cells of respiratory, arterial cells, gastrointestinal tract, and kidney - Hepatitis B: only affects liver cells of humansTropism----- of a virion or genome into host cell 1. penetration 2. uncoatingEntry of animal viral replicationEntire virion enters cell- by 2 mechanisms A. Direct fusion: ONLY enveloped viruses - enveloped merges directly with the cell membrane, liberating the nucleocapsid into the cell's interior B. Endocytosis: either enveloped or naked - happens when an entire virus is engulfed by the cell and enclosed in a vacuole or vesiclePenetration (a type of entry)Nucleic acid separates from protein coatUncoating (type of entry)Replication of viral genome and synthesis of viral proteins by the host cell's enzymes, tRNA & ribosomes 1. DNA viruses: enter the host cell's nucleus & are replicated and assembled there 2. RNA viruses: replicated and assembled in the cytoplasm 3. Retroviruses: turn their RNA genomes into DNASynthesis in animal viral replication1. Expression of viral genes 2. Replication of viral genomeSynthesis needs to accomplish what 2 things?Protein synthesis - Capsid proteins & enzymes required for replication - Often synthesized as polyprotein that is cleaved by viral proteases (a target site of antiviral medications) - NEED +ssRNA = mRNA - Then get viral protein synthesis by host cell machinery = TRANSLATIONExpression of viral genes- viral genome uses itself as a template - viruses evolve because they are sloppy & mutations occurReplication of viral genomeSloppy leads mutation & antigenic variationAntigenic driftViral enzymes are good targets for ------anti-viral drugsAttachment/absorption, entry (penetration & uncoating), synthesis thenBack to viral life cycle1. RNA dependent RNA polymerase a.k.a replicase lacks proofreading ability 2. Some RNA viruses have segmented genomesReplication of RNA viruses1. Generates mutations during replication- SLOPPY COPY 2. Results in antigenic variation called antigenic drift - Mutations in surface proteins may not be recognized by immune system. This is the reason for seasonal influenza & lack of immunityRNA dependent RNA polymerase a.k.a replicase lacks proofreading ability- When two different viruses or strains infect a host, new viral particles may contain segments from each virus sloppy assembly - New subtype results from this reassortment- process called ANTIGENIC SHIFT - this leads to a novel virus and & pandemic influenzaSome RNA viruses have segmented genomes- Mature virus particles are constructed from the growing pool of parts - Capsid is first laid down as an empty shell that will serve as a receptacle for the nucleic acid strand - If enveloped, viral spikes are inserted into the host cell's membrane so they can be picked up as the virus buds off with its envelopeAssembly1) nonenveloped/naked and complex viruses that reach maturation in the cell nucleus or cytoplasm are released when the cell lyses or ruptures 2) Enveloped viruses are liberated by budding from the membranes of the cytoplasm, nucleus, endoplasmic reticulum, or vesiclesRelease Assembled viruses leave their host in one of two ways:1. Size of the virus 2. Health of the host cell - poxvirus infected cell: 3,000 to 4,000 virions - poliovirus infected cell: 100,000 virions - immense potential for rapid viral proliferationThe number of viruses released by infected cells is variable, controlled by:1. Infect neighboring cells: remember interferon? 2. Travel through bloodstream or lymphatic system to other parts of the body A. Poliovirus: infect throat & intestinal tract B. Spread to motor nerves: paralysis C. Spread to CNS to cause meningitisAfter release, then what?Virus induced damage to the cell that alters its microscopic appearance 1. Gross changes in shape and size 2. Development of intracellular changes: inclusion bodies & syncytiaCytopathic effects and the typesCompacted masses of viruses or damaged cell organelles in the nucleus and cytoplasmInclusion bodiesFusion of multiple damaged host cells into single large cells containing multiple nuclei (giant cells) - accumulated damage from a virus infection kills most host cellsSyncytiaCollateral damage - malaise, fever, aches - overproduction of cytokines, usual progression of a cytokine storm if severe 1. Viremia viruses in blood 2. Systemic inflammatory response- sepsis 3. Septic shock: dramatic drop in blood pressure, DIC, organ damage and deathImmune response (damage to the host cell)Symptoms develop quickly and are over quickly ex: influenza, mumps, coldAcute viral infection2 types of chronic or latent infectionPersistent viral infectionsContinuous production of low levels of virus particles - person is a carrier ex: hepatitis BChronic infections- Provirus: viral DNA incorporated into the DNA of the host ex: herpes simplex and herpes zoster viruses -periodically virus becomes reactivated under the influence of various stimuli - stress, age, sickness & uv/light and sun. - Productive infection: releasing infectious virions - infectious during reactivation, non-infectious when latentLatent infectionsChronic - Hepatocytes (liver cells) - Hepatitis, cirrhosis, hepatocellular, carcinomaHepatitis B & C virusesLatent - B cells, which are involved in antibody production - Mononucleosis, Burkitt's lymphomaEpstein-Barr virusLatent - Neurons of sensory ganglia - Primary oral herpes or genital herpes and recurrent soresHerpes simplex virus type 1 & 2latent - Satellite cells of sensory ganglia - Chickenpox and shinglesVaricella zosterWhat is an example of a mixed virus with an acute, chronic, & latent phase?HIVDetermines host range and tropismAttachment CD4 and CCR5 marker in HIV1. Retrovirus: reverse transcriptase RNA to cDNA with enzyme integrase to form a provirus 2. Provirus: integrates into host DNASynthesis in HIV - retrovirus - provirusHigh number of virus particles - most infectious - vague symptoms: fatigue, diarrhea, weight loss, and sore throat - test HIV positive: by antibody test once seroconversion has taken place. 3-6 weeks post infection.Acute initial infection of HIVInfected macrophages and dendritic cells survive, but serve as a reservoir for replicating HIV - Mostly asymptomatic - Antibodies are high and levels of virus are low - if on anti-retroviral therapy & viral load is undetectable, then non-infectious - Helper T cells slowly killed by HIV infection; adaptive immune response weakensChronically shed virus in HIVSigns and symptoms of AIDS appear when helper T cell counts fall below 200 cells/microliter - AIDS: acquired immunodeficiency syndrome - fungal infections, mycobacteria, chronic herpes, & uncommon cancers (opportunistic infections) - Half of untreated patients progress to AIDS within 9 to 10 years - others with low viral set points survive many years. 1% of non-progressorsLatent disease in HIVCatalyzes the replication of double- stranded DNA from single stranded RNAReverse transcriptase------- can permanently integrate viral genes into the host genome that is passed on to progeny cells - some retroviruses also transform cells into cancer cells - HTLV-1 human T-cell leukemia virusRetrovirusesAll viruses associated with cancers are ------- infectionsPersistent-Experts estimate that 13% of ------ are caused by viruses A TUMOR is an abnormal mass caused by UNREGULATED CELL growth 1. Cancerous or malignant tumors can metastasize (spread) 2. Benign tumors do not spread or have their own blood supplyCancersThe effect of oncogenic, or cancer-causing viruses: - some viruses carry genes that directly cause cancer - Other viruses produce proteins that induce a loss of growth regulation, leading to cancerTransformation:1. Hepatitis B and C = liver cancers 2. Epstein-Barr = lymphomas 3. Human papilloma virus/genital warts = 99% of cervical cancer 4. Herpes virus = Kaposi's sarcoma in AIDS patientsType of cancerViruses that infect bacteria, a.k.a phages - most contain double stranded DNA, but some RNA types exist too - every bacterial species is parasitized by various specific bacteriophages - the bacteria they infect often become more pathogenic for humans - ALL ARE COMPLEX shape and NAKEDBacteriophages1. Lytic cycle 2. Lysogenic cycleTwo life cycles of bacteriophagesProductive infection- new virus particles released - virulent phages: T4 phage (dsDNA) is model - host cell dies with lysis - entire process takes approx. 30 minutesLytic cycleLatent infections 1. Temperate phage: Lambda phage is the model 2. Prophage: latent form of temperate phage whose DNA is inserted and is replicated along with host cell genome 3. Lysogens: bacteria that carry phage DNA (prophage) integrated into its genome 4. Induction: phage DNA is excised from bacterial chromosome and enters the lytic cycleLysogenic cycleWhen a bacterium acquires a new trait from its temperate phage - many toxin genes gained this way: botulism, diphtheria, hemolytic uremic syndrome E.coli: 0157:H7Lysogenic conversionListeria monocytogenes in 2006 & then others. C. jejuni, Salmonella & B. cereusBiocontrol in the food industry - uses of bacteriophagesUse of bacteriophages to treat bacterial infections - were used before antibiotic age. other countries continued. mostly abandoned by the US in the 1940s - with multi-drug resistant infections (TB, MRSA) phage therapy having a resurgence - in 2021, the U.S currently up to phase 2 clinical trials for multiple different treatmentsPhage therapyViruses must be grown in a appropriate host- require cells as their "medium". They are OBLIGATE INTRACELLULAR PARASITESCultivating viruses1. Isolate & identify viruses in clinical specimens 2. Prepare viruses for vaccine 3. Do research on viral structure, multiplication cycles, genetics, and effects on host cellsPrimary purpose of viral culture1. Animals: mice & rats 2. Embryonated (fertilized) chicken eggs 3. Cell culture or tissue culture is now commonly usedMethods used for cultivating viruses- observation of degeneration and lysis of infected cells - Plaques: areas where virus-infected cells have been destroyed show up as clear, well-defined patches in the cell sheet: - visible manifestation of cytopathic effects (CPEs)Direction of viral growth in culture:Are macroscopic zones of clearing from bacterial lysis - plaque-forming unit represents a single phage - counting plaques yields the titer, which is concentration of phage in the original samplePlaques:Used to detect and count phage particles in samples such as sewage, seawater, and soilPlaque assays