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Pathogenesis Virus

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Pathogenesis Virus

  1. 1. Virus pathogenesis and genetics www.freelivedoctor.com
  2. 2. Viral pathogenesis <ul><li>Cycle of infection </li></ul><ul><ul><li>Entry </li></ul></ul><ul><ul><li>Primary site replication </li></ul></ul><ul><ul><li>Spread within the host </li></ul></ul><ul><ul><li>Shedding </li></ul></ul><ul><ul><li>Transmission </li></ul></ul><ul><li>Effects on cells </li></ul><ul><li>Effects on organism </li></ul>www.freelivedoctor.com
  3. 3. Definitions <ul><li>Tropism </li></ul><ul><ul><li>what cells within the host does the virus infect? </li></ul></ul><ul><ul><li>influenced by cellular receptors, intracellular molecular restricitons, route of infection & spread </li></ul></ul><ul><li>Prodrome </li></ul><ul><ul><li>early disease symptoms which are mild or non-specific </li></ul></ul><ul><li>Fomite </li></ul><ul><ul><li>an inanimate object or substance that is capable of transmitting infectious organisms from one individual to another </li></ul></ul>www.freelivedoctor.com
  4. 4. Cycle of infection Secondary sites Spread Entry Shedding Shedding Local Lymphatic Neuronal Blood (viremia) Primary site www.freelivedoctor.com
  5. 5. Entry <ul><li>Mucous membranes or skin </li></ul><ul><ul><li>Respiratory </li></ul></ul><ul><ul><li>Oral </li></ul></ul><ul><ul><li>Sexual </li></ul></ul><ul><ul><li>Ocular </li></ul></ul><ul><ul><li>Percutaneous </li></ul></ul><ul><ul><ul><li>needles, wounds, bites </li></ul></ul></ul>www.freelivedoctor.com
  6. 6. Shedding, transmission <ul><li>Routes </li></ul><ul><ul><li>Respiratory </li></ul></ul><ul><ul><li>Gastrointestinal (oral-fecal) </li></ul></ul><ul><ul><li>Urogenital </li></ul></ul><ul><ul><li>Skin </li></ul></ul><ul><li>Mechanisms </li></ul><ul><ul><li>Indirect contact </li></ul></ul><ul><ul><ul><li>Aerosols </li></ul></ul></ul><ul><ul><ul><li>Fomites </li></ul></ul></ul><ul><ul><li>Direct contact </li></ul></ul><ul><ul><ul><li>Lesions </li></ul></ul></ul><ul><ul><ul><li>Saliva </li></ul></ul></ul><ul><ul><ul><li>Sex </li></ul></ul></ul><ul><ul><ul><li>Animal or insect bites </li></ul></ul></ul><ul><ul><ul><li>Maternal-neonatal </li></ul></ul></ul>www.freelivedoctor.com
  7. 7. Routes of entry and shedding www.freelivedoctor.com
  8. 8. Effects on cells <ul><li>Abortive infection </li></ul><ul><li>Lytic infection </li></ul><ul><li>Persistence </li></ul><ul><li>Transformation </li></ul><ul><li>Alteration of cellular metabolism </li></ul>www.freelivedoctor.com
  9. 9. Time course of infection; host response infection without spread: infection with spread: host response: www.freelivedoctor.com prodrome symptoms at secondary sites pro-drome symptoms at primary site healing innate immunity: interferon adaptive immunity: cellular, antibody inflammatory; immunopathogenesis 0 2 4 6 8 10 12 time (days)
  10. 10. Patterns of disease www.freelivedoctor.com
  11. 11. Mousepox pathogenesis www.freelivedoctor.com
  12. 12. Genetic principles <ul><li>Mutation </li></ul><ul><li>Selection </li></ul><ul><li>Recombination </li></ul>www.freelivedoctor.com
  13. 13. Scope of virus genetics <ul><li>Natural evolution of viruses </li></ul><ul><li>Clinical management of virus infections </li></ul><ul><li>Experimental virology </li></ul>www.freelivedoctor.com
  14. 14. Clinical significance of genetics <ul><li>Antigenic variation in HIV and influenza </li></ul><ul><ul><li>impact on vaccination </li></ul></ul><ul><li>Drug resistance in herpes and HIV </li></ul><ul><li>Reversion of attenuation in polio vaccine </li></ul><ul><li>Engineered vaccines </li></ul><ul><ul><li>temperature sensitive influenza (Flumist) </li></ul></ul>www.freelivedoctor.com
  15. 15. Mutation <ul><li>RNA virus polymerases lack proofreading function </li></ul><ul><li>RNA viruses mutate more frequently than DNA viruses </li></ul><ul><li>RNA virus &quot;quasi species&quot; are adaptable </li></ul>www.freelivedoctor.com
  16. 16. Mutant phenotypes <ul><li>Conditional lethal </li></ul><ul><ul><li>Host range </li></ul></ul><ul><ul><li>Temperature sensitive </li></ul></ul><ul><ul><li>Drug dependence </li></ul></ul><ul><li>Drug resistance </li></ul><ul><li>Plaque morphology </li></ul>www.freelivedoctor.com
  17. 17. Temperature sensitivity No growth Grow virus Phenotype virus www.freelivedoctor.com wt wt wt high temp low temp
  18. 18. Temperature sensitive mutants <ul><li>Genotype </li></ul><ul><ul><li>Single amino acid substitutions </li></ul></ul><ul><li>Mechanism </li></ul><ul><ul><li>Protein unstable, non-functional at an high temperature </li></ul></ul><ul><ul><li>Protein stable, functional at a low temperature </li></ul></ul><ul><li>Isolation </li></ul><ul><ul><li>Random mutagenesis </li></ul></ul><ul><ul><li>Brute force screening for growth at two temperatures </li></ul></ul><ul><ul><li>Targeting possible </li></ul></ul><ul><li>Advantages </li></ul><ul><ul><li>Accesses any essential virus gene using a single set of protocols </li></ul></ul>www.freelivedoctor.com
  19. 19. Temperature sensitivity wt 31 o C wt 40 o C ts 31 o C ts 40 o C www.freelivedoctor.com
  20. 20. Drug resistance wt -IBT wt +IBT mut -IBT mut +IBT www.freelivedoctor.com
  21. 21. Recombination and reassortment <ul><li>DNA viruses </li></ul><ul><ul><li>Breaking and joining </li></ul></ul><ul><li>Non-segmented RNA viruses </li></ul><ul><ul><li>“ copy choice” </li></ul></ul><ul><li>Segmented RNA viruses </li></ul><ul><ul><li>“ reassortment” </li></ul></ul><ul><li>Impact </li></ul><ul><ul><li>Intrinsically interesting </li></ul></ul><ul><ul><li>Virus evolution </li></ul></ul><ul><ul><li>Laboratory virology </li></ul></ul>www.freelivedoctor.com
  22. 22. DNA virus recombination www.freelivedoctor.com
  23. 23. RNA virus recombination Copy choice www.freelivedoctor.com
  24. 24. RNA virus reassortment www.freelivedoctor.com
  25. 25. Summary: Pathogenesis & Genetics <ul><li>Effects on cells </li></ul><ul><ul><li>Abortive, lytic, persistent, latent, transforming infections </li></ul></ul><ul><li>Cycle of infection </li></ul><ul><li>Effects on the organism </li></ul><ul><li>Genetics </li></ul><ul><ul><li>Mutation, genotype, phenotype, reversion, recombination </li></ul></ul>www.freelivedoctor.com
  26. 26. For each virus, know: <ul><li>Structure </li></ul><ul><li>Pathogenesis </li></ul><ul><ul><li>transmission/entry/shedding </li></ul></ul><ul><ul><li>replication </li></ul></ul><ul><ul><li>spread </li></ul></ul><ul><ul><li>immune response/counter response </li></ul></ul><ul><ul><li>damage/disease mechanism </li></ul></ul><ul><li>Diagnosis </li></ul><ul><li>Treatment/prevention </li></ul><ul><ul><li>drugs </li></ul></ul><ul><ul><li>vaccines </li></ul></ul>www.freelivedoctor.com

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