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