pathogenesis virus

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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