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233 Cards in this Set

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Koch's Postulates
- agent must be present in all cases of the disease
- agent must be isolated and grown in vitro
- disease must be produced when a pure culture is inoculated into a susceptible host
- the same agent must be recovered again from the experimentally infected host
Who developed the 1st attenuated vaccine?
What was the agent?
Pasteur

rabies virus
What techniques are used to grow viruses?
eggs

cells & tissue cutures

genetic material, enzymes
definition of a virus
- genetic material is either DNA or RNA
- simple strx (protein shell surround nucleic acid, with or without envelop)
- replicate only in living cells
- no energy yielding apparatus
- no binary fission
- not susceptible to most bacterial antibiotics
regressive theory vs cellular theory of virus evolution
regressive
- degenerate parasites

cellular
- derived from cellular components
virion
mature virus particle
capsid
protein coat
capsomere
capsid subunit
nucleocapsid
nucleic acid + protein shell
peplos
lipid envelope
peplomer
projections on some envelopes

usually glycoproteins
chemical units refer to
polypeptide chains of capsomere
a nucleocapsid without a genome is ______
a capsid
physical properties of viruses
Repeating units with spatial regularity.

Small amount of genetic information.

Protein subunits assemble spontaneously.

Limits variety of morphology:
- cubic, binal, complex, helical
viral shapes
Cubic
- Icosahedral
- 12 vertices, 30 edges, 20 faces

Helical
- Spiral
- Coiled or rod-shaped

Binal
- Combination of cubic and helical.
- Phages

Complex
- No distinct morphology.
- Poxviruses
helical virus
complex virus

(no distinct shapes)
Are enveloped or non-enveloped viruses more pleomorphic?
enveloped
enveloped virus

herpesvirus
infectious genome
Purified nucleic acid is infectious
viral nucleic acid (excluding retroviruses) is ______.
(haploid or diploid)
haploid
DNA viruses
Usually single molecule of ds DNA; some are ss DNA.

Linear or circular

4.5-200kb

Differential splicing and open reading frames increases coding capacity.
RNA viruses
Usually ss RNA, few ds RNA.

May be single molecule or segmented.

Majority are linear.

Considerable 2o structure.

+ and – sense (most + have poly-A tail and cap)

7.5->20kb
ss RNA genomes
+ve and -ve RNA genomes

Positive – same sense (sequence) as mRNA
- Same sequence as RNA
- Can be translated by ribosomes

Negative – complement (mirror sequence) of mRNA.
- Complementary to the RNA
- MUST be transcribed to mRNA before translation.
______ must undergo translation in order to be infectious.
(pos sense/ neg sense)
neg sense
viral proteins
Structural or nonstructural.

Protects nucleic acid.

Peplomers usually glycoproteins.

Surface proteins responsible for attachment to cell surface receptors.

Enzymes
structural vs. non-structural proteins
Non-structural are expressed only in the infective state

Structural are carried in the virion
surface proteins of enveloped vs. non-enveloped viruses
Enveloped viruses = surface proteins (peplomere) involved in attachment
- Remove the lipid membrane, and the virus is no longer able to infect b/c can’t attach to target cell
- Soaps/ detergent work on this

Non-enveloped viruses = surface proteins (capsomere) involved in attachment
- Have to use bleach and other stronger treatments to inactivate the virus
viral lipid is of ______ origin
cellular
viral lipid and carbohydrate
Lipid is of cellular origin.

Envelope mediates attachment, fusion and entry of a virus; released by budding.

Carbohydrate usually is component of peplomers; important in antigenicity of the virus.
- Virus encodes glycoprotein, inserted in cell membrane (RER).
- Piece of cell membrane “stolen” by virus as it leaves the cell
virus classification
Order – virales

Family – viridae

Subfamily – virinae

Genus – virus

Species – often a number

Serogroups, strains, variants…..

The phylogenetic relationships implied may not be accurate, as origin is unknown.
how do we classify viruses

(based on what characteristics)
Structure
- DNA or RNA
- Single molecule or pieces
- Circular or linear
- Enveloped or not
- Symmetry?

How stable is it in the environment
- Easy to inactivate with heat or freezing and thawing

How does it replicate & where in the cell it replicates
- Some do everything in nucleus except replicate in cytoplasm

Biologic properties
- Antibodies
- Host range

How does it spread
- From animal to animal or environment to animal

Where does it target in the animal?
- Skin or lungs or etc.
_______ & ________ are used to classify viruses
morphologic features & chemistry
6 features used to classify viruses
Properties of the genome.
- Nucleic acid type
- N.A. size, sequence

Properties of the virion.
- Capsid symmetry
- Enveloped?
- Diameter

Properties of proteins.
- Size, function, sequence

Physical properties.
- Stability in varied circumstances

Replication strategy.
- Entry, transcription, genomic replication, assembly, release
- Locale in the cell

Biological properties.
- Serology, host range, antigenicity, tissue tropism, transmission, vector, epidemiology, etc
Do DNA or RNA viruses have a higher mutation rate
RNA viruses (1/1000)

DNA is only (1/1mil)
retention of mutation depends on what
Selective advantage

Stage of infection
name 2 ways that mutations can be classified
classified according to the type of change in the nucleic acid

classified by their phenotypic expression
phenotypic mutants
Mutation leads to detectable change in the virus; e.g. antigenicity, replication requirements, disease produced…

Plaque morphology mutant
- How does it destroy the cell
- Does it destroy 1 cell at a time or widespread

Host range mutant

Temperature sensitive mutant
- FIP vaccine (only replicates at cool temp)
- No systemic spread

Nonsense mutation

Deletion mutation

Drug resistance mutant
______ is compensation for lethal mutations between viruses
genetic reactivation
______ is exchange of nucleic acid sequences between viruses
recombination
types of recombination
Breakage-reunion
- 2 viruses replicating in same cell and cut & paste can be b/w viruses or b/w viral DNA and mRNA
- all viruses

Template switching
- in any virus

Reassortment
- Only in viruses whose genetic material is in pieces
- Influenza (every gene is on a separate piece of genetic material)
- Get mixing of segments from 2 different influenza viruses
what types of viruses can exhibit recombination by reassortment?
segmented viruses
what types of viruses can exhibit recombination by breakage-reunion?
all viruses
what types of viruses can exhibit recombination by template switching?
all viruses
describe template switching
recombination event between 2 viruses, not by cutting and pasting, but by switching the template
give an example of a recombination event
Sometimes FeLk reactivates (provides missing piece) for the virus that was defective and sitting in the cell

If you’re missing a polymerase, I’ll give you mine
interactions between gene products (proteins)
complementation
- exchange of gene products

Phenotypic mixing
- Transcapsidation
- Envelope protein mixing
- polyploidy
describe transcapsidation
mixed infection leads to

Hybrid virus in 1st generation

Subsequent generations go back to the original b/c the genetic material hasn’t changed
what types of viruses can exhibit recombination by template switching?
all viruses
describe template switching
recombination event between 2 viruses, not by cutting and pasting, but by switching the template
give an example of a recombination event
Sometimes FeLk reactivates (provides missing piece) for the virus that was defective and sitting in the cell

If you’re missing a polymerase, I’ll give you mine
interactions between gene products (proteins)
complementation
- exchange of gene products

Phenotypic mixing
- Transcapsidation
- Envelope protein mixing
- polyploidy
describe transcapsidation
mixed infection leads to

Hybrid virus in 1st generation

Subsequent generations go back to the original b/c the genetic material hasn’t changed
reassortment is accomplished by antigenic ______
(shift or drift)
shift
the purpose of antigenic shift in nature
alteration of antigenicity offers selective advantage
antigenic shift vs antigenic drift
antigenic drift
- Can mutate w/in itself just by making random mistakes copying its genome
- small change

antigenic drift
- Sometimes segments are exchanged b/w 2 different flu viruses infecting the same cell at the same time
- big change
- change in whole gene, not just a few nucleotides
attenuation
What was originally a highly lethal virus became a not serious disease

myxomatosis
define viral epidemiology
Study of factors that determine the frequency and distribution of viral diseases.
What role does mechanism of transmission play on viral epidemiology?
Entry and shedding

Respiratory, enteric, contact, injection, congenital.

Influenced by route and duration of shedding, hardiness in environment, existence of reservoirs.
define incidence
# of cases in a time period
prevalance
# of cases at one time point
morbidity vs. mortality
morbidity
- % of population that develops disease during an outbreak

mortality
- % with disease that die
endemic
disease occurs continuously in a population over a period of time
epidemic
peaks in disease that exceed expected incidence
pandemic
worldwide epidemic
high morbidity suggests that an agent is _______ to spread
(easy/ hard)
easy
modes of transmission
Direct – requires physical contact

Indirect – can involve fomites (inanimate objects), airborne (no animal to animal contact, just shared air space)

Vector

Iatrogenic – by YOU!

Nosocomial – in hospital

Zoonotic – animals to humans (sometimes the reverse!)

Vertical – dam to offspring
influenza
highly virulent = _____ period of transmission
(shorter or longer)
shorter
virulence
Impacts period of communicability

e.g highly virulent = shorter period of transmissibility
how does community size affect disease transmissibility
Need continuous supply of susceptible individuals.

Population density also important – rate of spread is decreased if the population is spread out, break in chain more likely.
describe how the population density differs in the transmission of parvo vs. distemper (canine)
Parvo in dog doesn’t need a large population to be spread
- It can be shed in environment and then 7 mo later another dog comes around and gets it.

Distemper only lasts a few days in order to be able to spread by indirect contact
- So normally need direct contact
persistent infection
continual shedding and introduction into a population.

Need smaller population to maintain
vertical transmission
Across placenta

Germ line

During birth

Breast milk
do persistent infections need a large or small population? why?
Don’t need a large population b/c long shedding from carrier
does a wide host range increase or decrease the chance of successful transmission
increase

See in arboviruses b/c arthropods feed on many spp.
how does season affect virus transmission
Arboviruses (more arthropods present in fall than spring)

Environmental conditions

Management changes, e.g housing indoors
acute vs persistent infection
Acute infection/disease has a relatively rapid course.
- Incubation period of days to weeks.
- Clearing of virus within 2-3 weeks of disease onset.

Persistent infection may last months or years.
what are the 4 patterns of disease and give an example of each.
acute
- parvo

recurrent
- callisivirus

chronic
- FIV

slow
- prion dz
what is the importance of persistent infection?
May be reactivated and cause acute episode, or cause a late sequela to infection.

May be associated with immunopathological disease.

May lead to neoplasia.

Important epidemiologically due to recurrence of or continual shedding.
late complications of acute dz
Virus may persist, e.g. brain with CDV;

or effect not detected until later time point, e.g. viruses causing abortions.
latent infection
No virus shedding when latent.

Intermittent recrudescence of latent virus with shedding.

Herpesviruses
chronic infection
Virus is always demonstrable.

HIV, FIV
slow infection
Long incubation period followed by slow progressive disease.

“mad cow disease”
types of persistent infections
Late complications of acute infection.
- Virus may persist or effect not detected until later time point

Latent infection
- No virus shedding when latent.

Chronic infection
- Virus is always demonstrable.


Slow infection
- Long incubation period followed by slow progressive disease.
what are the stages of viral infection (after inoculation) and how many viral particles are present at each stage?
eclipse phase
- virion taken into cells quickly after inoculation

maturation phase
- virions released from cells to infect new cells

begins to fall off b/c all the cells have been killed by the virus
which type of viral infection can lead to neoplasia?
abortive
3 types of viral infections
productive
- virus will be shed (released from cell & host)

abortive
- virus enters cell, but can't complete replication
- can lead to neoplasia

restrictive
- virus will grown in certain circumstances but not others (restrictions on where virus can replicate)
tropism refers to
The virus must be able to infect a cell.
Know the stages of viral infection starting from attachment
virus attachment
Chance meeting

Binding mediated via cell receptors

Susceptibility determined by the cell receptor

Susceptibility + ability of the cell to support virus replication
determines the host range
viral penetration
Virus penetrates into the cell
“disappears”

Three major mechanisms
Endocytosis - nonenveloped and enveloped
Fusion - enveloped only
Translocation - nonenveloped only

Majority fail
what mechanism of penetration is used by enveloped viruses
Endocytosis or Fusion
what mechanism of penetration is used by non-enveloped viruses
Endocytosis or Translocation
endocytosis & fusion
(enveloped virus)
______ allows transcription to occur
virus uncoating
virus uncoating
Release of n.a.

May occur in cytoplasm or nucleus

Allows transcription
to occur
where does virus uncoating occur
in cytoplasm or nucleus
the product of virus transcription is
RNA
virus transcription
Product is RNA.

ssRNA+ viruses bind directly to ribosomes for translation – do not have to undergo transcription first.

ALL other RNA viruses must undergo transcription first.

DNA viruses that replicate in the nucleus may use cellular enzymes (DdRp).

All others require unique transcriptase.
- virus encoded – the cell has NO enzyme that copies RNA into RNA (RdRp)
- carried into the cell or immediately translated
Virus transcription for DNA viruses
Transcription is sequential.
- Early, late

Important step in regulating gene expression.
- Promoter control
- termination signal
- splicing
- rate of degradation

“Genetic Economy”
- both strands
- gene overlap
- different ORF
- variation in termination and splicing
Virus Transcription
RNA Viruses
More complicated; no clear early and late phase.

(-) strand - transcription by virion-associated transcriptase.

(+) strand - translation produces virion-associated transcriptase.

dsRNA - segmented - each a unique gene; undergo transcription first using virion-associated transcriptase.

Retroviruses - reverse transcribed to ds DNA , then mRNA transcribed.
how are retroviruses transcribed?
reverse transcribed to ds DNA , then mRNA transcribed.
dsRNA virus transcription
segmented
- each a unique gene

undergo transcription first using virion-associated transcriptase.
virus translation
mRNA translated by cellular ribosomes; product is protein.

Uses cellular machinery.
- Monocistronic vs. polycistronic messages.
- Monocistronic – one gene→one protein
- For polycistronic messages: Internal initiation of transcription; Polyprotein that is cleaved; or Translate only the first ORF.

ONE message → One protein
monocistronic vs. polycistronic messages
Monocistronic
- one gene→one protein

polycistronic messages:
- Internal initiation of transcription; Polyprotein that is cleaved; or Translate only the first ORF.
describe how a virus gets genetic economy but still fits the rule of 1 message -> 1 protein
Sometimes the virus can fold their single stranded mRNA and get a 2nd product produced
- Internal ribosomal entry site allows the 2nd translation (polycistronic message) but it is seen as monocistronic to the ribosomes


Cellular ribosomes recognize only 1 message on a mRNA

There may be splicing that occurs but the product is only 1 protein

As far as ribosomes are concerned, all are monocistronic

But as far as the virus is concerned, it may get several proteins out of 1 piece of mRNA
Do pos sense RNA viruses tend to be mono or polycistronic?
polycistronic

Tend to make a big protein and cut it up
Do neg sense RNA viruses tend to be mono or polycistronic?
monocistronic

Make each strand individually
describe nested transcription
all protein products share a 3' end but they have different 5' ends (start at different points on the strand)

Only unique, 5’-most ORF is translated
early vs late proteins
Early proteins (before genome is copied) are generally enzymes.

Late proteins (after genome is copied) are generally structural.
how do viruses make a capsid?
No cellular machinery to make a capsid

After proteins form, they crystallize together to form a shell
replication of nucleic acid
DNA viruses
- similar to cellular DNA; product and template are DNA.
- May use cellular enzymes.

RNA viruses – product and template are RNA
- MUST use viral enzyme
(+) --> full length (-) --> full length (+)
(-) -->full length (+) --> full length (-)

Retroviruses:
RNA --viral enzyme--> dsDNA ---->integrates into cellular DNA --cellular enzyme--> RNA
how are viruses released from the cell?
cell lysis

budding
for enveloped, how is the membrane acquired
membrane acquired by budding through cellular membrane
what happens after replication of the genome?
Structural proteins synthesized.

Proteins aggregate spontaneously.

virus is released by cell lysis or budding.
when does a virus mature?
after release from the cell
attachment exploits ______
a cellular protein
circoviridae

non-enveloped (cookie cutter shaped)
adenoviridae

Icosahedral nonenveloped virus
Icosahedral nonenveloped virus

adenoviridae
Icosahedral nonenveloped virus

adenoviridae
parvoviridae

small, icosahedral capsid

non-enveloped
parvoviridae

small, icosahedral capsid

non-enveloped
circoviridae

Nonenveloped, icosahedral capsids
circoviridae
papovaviridae

Icosahedral capsid.
Nonenveloped
Icosahedral capsid.
Nonenveloped

papovaviridae
parvovirinae is associated with what types of animals?
vertebrates
parvovirus
veterinary pathogen
erythrovirus
human B19
aleutian mink disease is associated with what virus
ambovirus

(parvovirinae)
bocavirus
Bovine parvovirus and minute virus of canines

human bocavirus – respiratory, gastroenteritis in infants – role unclear
what parvoviridae are associated with invertebrates
Densovirinae – insects, other invertebrates
- Densovirus
- Iteravirus
- Brevidensovirus
- Pefudensovirus
_______ is the smallest animal virus
parvovirus
describe parvovirus
18-26nm

Icosahedral capsid, 32 capsomers.

3 proteins – VP1-3

No envelope nor enzymes in mature virion
describe parvovirus's genome
ssDNA genome
- 5-5.5kb
- Negative sense
- Y-shaped hairpins at both ends due to palindromic sequences.

2 major ORF’s
Left half – 2 NS proteins
Right half – 3 coat proteins
why do parvoviruses need rapidly dividing cells?
b/c they don't produce any enzymes that can push the cell into the cell cycle.
parvovirus replication
Replicates in nucleus.

Depends completely on host cell enzymes.

Replicates in cells of “high mitotic index.”
- Bone marrow
- Intestinal crypts
- Fetus

Virus does not encode replication enzymes such as polymerase.

Uses cellular DNA polymerase and RNA transcriptase

Uses cellular splicing machinery
where does parvovirus replicate?
in the nucleus of rapidly dividing cells (intestinal crypt, bone marrow, fetus)
describe parvo replication (ORF/ proteins made)
3’ORF encodes VP1-3.
5’ORF encodes NS1-2.
- Regulate gene expression.
- Function in DNA replication – helicase, endonuclease, nicks cellular DNA to inhibit its replication.

VP1 and VP2 formed by alternative splicing of same mRNA.

VP3 formed by cleavage of amino acids from VP2.
parvo genomic replication is primed by _______
primed by hairpins.

Complex replication, with circular ds intermediates and concatemers.
describe parvo entry through replication of genome
Virus will attach to cell surface molecule

Magically gets into cell

Traverses to nucleus

Uncoats and releases its genome

Transcription to make mRNA
2 mRNA for 2 genes (structural and non-structural)

Differential splicing allows virus to get 2 products from this 1 protein (NS1 & NS2)

For structural proteins, they start at different initiation points (VP1 & VP2)

Structural protein 3 is produced from further proteolytic processing from the VP2
describe the importance of hairpins/ concatemers for parvo replication
Hairpins serve as primers for host cell enzymes to start copying the genome

Cut up into individual pieces by viral particles


Concatemers (multiple copies
of the genome) are formed,
cleaved by viral endonuclease
how does exposure to parvo occur?
oronasal exposure

(not ingestion)
where does parvo replicate
in lymphoid tissue

Replicates in cells of high mitotic index
- Bone marrow
- Intestinal crypts
- Fetal tissue (can cause abortion)
how is parvo shed?
Shed in feces (dogs, cats, others), aborted material and semen (swine)
describe parvo in dogs (direct result and secondary action)
Can get profound leukopenia which is dangerous in itself

Combine that with the damage of the intestinal epithelium and you get a secondary sepsis
describe parvo disease syndromes of veterinary importance (4)
Panleukopenia of cats.

Hemorrhagic enteritis in dogs.

Abortion and stillbirth in swine.

Aleutian mink disease.
describe parvo in humans
5th disease

slapped cheek

aplastic crisis in pt with underlying hemolytic dz

fetal infection

inclusions in RBC precursors
feline panleukopenia
Parvo
- mucosal destruction
- villous atrophy
- cerebellar hypoplasia

Infects all Felidae (including exotic felids)

Profound leukopenia (decreased WBC’s) due to replication in bone marrow.

Vomiting, bloody diarrhea, depression.

Neonates suffer cerebellar hypoplasia.

Spread by direct and indirect contact.

Vaccination with killed or modified live vaccines.
canine parvovirus dz
CPV 1 – minute virus of canines – mild disease if any.
- Fetuses and neonates only
- Wipes out puppies very rapidly (almost no signs of dz)

CPV 2 – a “new” virus.
- Emerged in late 70’s worldwide.
- All canids susceptible.

Similar symptoms to FPV – intestines, bone marrow.

Myocarditis in neonatal pups.
how does parvo infection differ from other enteric viruses
Most enteric viruses target mature cells at tip of villus causing malabsorption

Parvo targets crypt cells so no ability to regenerate intestinal epithelium
describe canine parvovirus vaccinations/ recent mutations
Disease primarily occurs when maternal immunity wanes.

Killed and modified live vaccines.
- Killed only in utero or just after born
- All others get modified live


Mutations led to appearance of new strains 2a and 2b in 80’s; recently 2c has emerged.
- Reacquired ability to replicate in cats.

All strains are not in the vaccine, but they are cross protective.
swine parvo
Swine: fetal tissue.
- Embryonic death, mummification, stillbirth, birth of weak pigs depending on stage of gestationg.

Recovered animals may be carriers.

Killed and modified live vaccines in gilts.


Variation in tropism among species probably related to expression of appropriate cell receptor.

Neutralizing antibody important in protection.
goose & duck parvo
Lethal to goslings and Muscovy ducklings –
Hepatitis, myocarditis
rodent parvo
Common in lab colonies.

Fetal death.

Subclinical carriers.

Affect immune response, confounds research.
aleutian dz
Immune-mediated

Virus not eliminated, immune complexes form.

Mink homozygous of pale (“Aleutian”) coat color susceptible.

Glomerulonephritis, vasculitis, hepatitis, anemia and death.

See bone marrow problems, intestinal problems, and immune system diseases

The outlier is aleutian disease b/c of immune complex formation

Skin, renal disease, anemia, etc.
how do you detect parvovirus
Usually look for virus itself not by antibody detection b/c lots of animals have antibodies
how do you destroy parvovirus
Something with detergent will get rid of this (ammonia won’t work) need oxidizing agent
parvo dx & tx
Symptoms
- Enteric - Identification of virus by EM or ELISA.
- Virus isolation, immunofluorescence of tissue (esp fetus).
- Serology for antibody detection.

tx
- Supportive treatment.
- Control in veterinary medicine through vaccination.
- Disinfectants must have oxidizing agent as active ingredient
Circoviridae genera
Circovirus – porcine, psittacine circoviruses, other avian circoviruses (pigeons, finches, doves among others).

Gyrovirus – chicken anemia virus.

Viruses share no antigenic determinants nor DNA homology with one another.
is circoviridae a high risk for mutation or not?
Very little genetic homology so not a high risk of mutations
how does circoviridae compare to parvo?
Both single stranded DNA

Target rapidly dividing cells

The difference is their genome
- Smaller genome than parvo
- But that genome has 3-4 genes depending on strain
circoviridae properties
Nonenveloped, icosahedral capsids, 17-22nm.

Circular ssDNA, ambisense (porcine, psittacine) or negative sense (chicken), 1.7-
2.3kb.

3-4 ORF’s.

Single protein forms capsid

Some have apotin which induces apoptosis of T cells.

Stable in the environment
circoviridae replication
Occurs in the nucleus.

Similar to parvovirus, probably depends on cellular proteins produced in S phase of cell cycle.

Genome replication occurs via rolling circle.

Post-translational cleavage may occur.
where does circoviridae replication occur?
in the nucleus
describe how the circoviridae genome is copied
Circular so different way of copying the genome

Some regions of the genome are the same sequence as the mRNA

Some regions are the complement of the mRNA

So it has both pos and neg sense (ambisense)
where does circoviridae target in a bird
Rapidly dividing cells in the bird are feather follicles and beak

Also goes for WBC and occ digestive problems
psittacine beak and feather disease
Chronic disease of psittacines characterized by feather dystrophy and loss, beak abnormalities.

PBFDV 1 and 2 (latter in lories) - circoviruses

Generally a disease of young birds.

Necrotic abnormal feathers.

Beak deformities develop later.

Pneumonia, enteritis due to secondary infections.

Occurs worldwide.

Endemic in wild populations.

Similar virus in doves in Australia.

Targets epithelial cells (dividing cells of basal layer) leading to feather necrosis and abnormal beak formation.

Also necrosis of thymus and bursa of Fabricius(!)

Shed in feather dander, droppings.

Vertical transmission via egg does occur.

Carrier state may occur.

Inhaled or ingested, spreads systemically.

Immunosuppression occurs.
- Due to thymus and bursa atrophy.
porcine vasculitis
circovirus

PCV 1
- Widespread in pig populations.
- May be a fetal pathogen.

PCV 2
- Young pigs with wasting disease syndromes – postweaning multisystemic wasting syndrome (PMWS).
- Respiratory disease, pneumonia.
- Dermatitis (due to necrotizing vasculitis) and nephropathy – immune-mediated?
- Reproductive disease, enteritis, CNS disease.
wasting syndrome (pigs)
Major economic concern

Occurs worldwide

Depleted lymphocytes

Virus found in lymphocytes, monocytes, macrophages, as well as lung.

Concurrent infection with other pathogens

Wasting, failure to thrive; enlarged lymph nodes

Nursery age piglets.

Mortality of 10% and higher.
chicken anemia virus
Gyrovirus (Circoviridae)

Occurs worldwide.

Chicks susceptible; resistance increases with age.

Transmitted by direct and indirect contact, and through the egg.

Viremia develops after exposure.

Virus replicates in RBC precursors, thymus (incl T helpers), and spleen.

Infection leads to decreased erythropoiesis and anemia, and immunosuppression.

Mortality may be as high as 50%, usually less.

Diagnose with signs, pathology, and virus isolation; serology can be done.

Vaccine available in Germany.
papovaviridae subfamilies
papillomaviridae

polyomaviridae
is adenoviridae capable of causing oncogenesis in natural infection?
no

only seen experimentally
is papillomaviridae capable of causing oncogenesis in natural infection?
yes
papillomaviridae vs. polyomaviridae
Papillomaviridae
- Cause warts in animals.
- Associated with oncogenesis experimentally and in natural infection.
- Many groups distinguished antigenically.
- Given separate genera designations. Greek letters,(Alphapapillomavirus, Betapapillomavirus, etc.) Or referred to by host.
- Many types determined by DNA sequence.

Polyomaviridae
- One genus - Polyomavirus
- Rare disease in humans.
- Significant veterinary pathogen. (Pathogen of psittacines.)
- Oncogenic only in experimental systems.
is polyomaviridae capable of causing oncogenesis in natural infection?
no

only experimentally
compare papovaviridae to parvo/ circo/ adenoviridae
Spherical (icosahedral) virus

Twice the size of parvo

½ the size of adeno

More complex than parvo and circo but still pretty small

Circular (covalently closed) genome
papovaviridae properties
Icosahedral capsid.
- Nonenveloped.
- 45-55nm diameter.
- 72 capsomers.
- Three viral proteins make up the capsid of polyoma-, two for papillomavirus.

dsDNA
- Covalently closed circle.
- 5-8kbp.
- Genome is divided into early and late regions.
- Noncoding elements control transcription and replication.
early region vs late region of genome
Early region
- Those proteins expressed before replication
- Proteins used for replicating the virus
- Regulatory fxns in transcription, gearing up the cell, etc.
- Non-structural proteins (don’t leave the cells with the virus)

Late region
- Those proteins expressed after the DNA is synthesized
- Makes up the protein shell of the virus
- Structural proteins
papovaviruses' replication
Replicates in nucleus of cell.

Receptor unknown; may be growth factor receptor.

Enters by endocytosis, uncoats in nucleus.

Early and late phases of transcription.
- Early phase done by cell RNA polymerase.

Very complex control of transcription.
where does papovavirus replicate?

where does it uncoat?
in the nucleus

in the nucleus
describe papovaviridae from attachment through replication
Attaches to the cell surface (receptor unknown)

Endocytosed into cell

Magically translocates into nucleus where it uncoats

Early transcription by cellular polymerase (DNA dependent RNA polymerase)

Non-protein encoded regions of genome are impt regulators of transcription (steals the host polymerase)

When enough of the non-structural proteins are made, switches to transcription of the genome
polyomavirus replication
Early mRNA is transcribed from one strand, while late mRNA is transcribed from the other strand.

Early proteins are T antigens – 2-3 proteins.
- Coding regions overlap.
- Significant splicing of mRNA.
- Alternative splicing leads to different proteins from same ORF.

Products activate cellular genes leading to DNA synthesis.
polyomavirus DNA replication
DNA replication
- similar to chromosomal replication.
- Depends on cellular enzymes.
- Begins at origin, proceeds in both directions.
- Early proteins initiate replication and unwind helix.
polyomavirus late transcription
Follows DNA replication.

Structural proteins of capsid.

Alternative splicing of mRNA, use of different initiation codons and reading frames produce capsid proteins VP1-3

Transported to nucleus for assembly

Release due to cell death.
- May be induced.
- May be a result of natural turnover.
papillomavirus has a specific tissue tropism for ______
squamous cells

infects basal cells
how is papillomavirus shed?
in exfoliated cells
papillomavirus replication
Early and late transcription.

Transcription very complex – multiple promoters, complex splicing, regulation of mRNA production.

9-10 ORF’s – 7-8 early genes, 2 late genes.

Early proteins induce cellular hyperplasia via early proteins; mass into papillomas.

Late transcription and translation occur in terminally differentiated cells.

DNA replication similar to polyomavirus.
why can't we culture papillomavirus?
we can't mimic the differentiation process
why are papillomaviruses associated with tumors?
Virus is promoting the growth of the cell
- In productive infection that is okay b/c cell will be destroyed


Genome persists, usually episomally; can integrate into cellular DNA.

Early proteins expressed, lead to transformation.

Affect growth factors, other cellular factors.

Cofactors required for malignancy.

Cervical cancer in women; gastric carcinoma in Scottish cattle.
polyomavirus
Rare

BKV
- Entry into respiratory tract.
- Spreads via blood.
- Eventually to urinary tract.
- Usually inapparent.

JCV
- Progressive multifocal leukoencephalopathy.
- Complication of certain immunosuppressive or malignancy disorders.
avian polyomavirus
Occurs worldwide.
- First identified in budgies.
“budgerigar fledgling disease”
- Infects all psittacines, some nonpsittacine, e.g. finches.

Virus is shed in droppings, dander, oral secretions; vertical transmission may occur.

Disease development is age dependent.
- Nestling and juvenile birds most susceptible.
- Disease in adults is rare.


Virus replicates in wide variety of tissues.
- Viremia occurs after entry.
- Infects endothelial cells, hepatocytes, renal tubules, monocytes/macrophages.

Acute death in birds <2 weeks of age.
- Hepatic necrosis
- Ascites, hyeropericardium, neurologic signs.

Dysplastic feathers in those that develop signs after 2 wks of age.
- Symmetrical.
- May be the only sign.
- Results from damage to blood vessels supplying the feathers

no tx but vax available
papillomavirus disease
Enters through skin abrasions.
Infects basal cells; early proteins induce hyperplasia.

Usual outcome is benign growth.

May persist for months or years, or may regress spontaneously.
papillomavirus lesions
Common warts
- Areas subject to abrasions.

Flat or planar warts
- children

Plantar/palmar warts
- Weight-bearing areas

Epidermodysplasia verruciformis.
- Wide distribution, associated with immunosuppression.

Genital warts
- Mucosal not cutaneous

Laryngeal papillomas
- Children.
what is papillomavirus's role in cancer
HPV detected in 93% of cervical cancers.

Viral DNA remains un-integrated.

Nonproductive infection.

Involves early gene products.

Inhibit growth arrest, degrade tumor suppressor protein.
bovine papillomas
Common.

Affects all ages, but highest incidence in calves.

Enter through skin abrasions.
- Fomites such as halters, nose tongs, posts important in spread.

Fibropapillomas or epithelial papillomas depending on virus species.

Papillomas persist for months, then spontaneously regress.

Associated with gastric and urinary bladder carcinomas in Scottish cattle.
- Ingestion of bracken fern contributing factor
equine papillomas
Often around nose and lips.

Regress after several months.

Sarcoids are skin tumors that persist for life and are locally invasive.
- Several types based on appearance and growth characteristics.

Horses are susceptible to infection with some bovine papillomas – may be the cause of sarcoids.
canine papillomas
Usually begin on lips, spread to mucosa, tongue, palate, pharynx.

Regress spontaneously.

If block airway, may require surgery.
papillomas in birds
Finches, psittacines.

In finches, papillomas occur on legs.
the legendary jackelope may be associated with what virus
papillomavirus
dx, tx, control of polyomavirus
Diagnose with virus detection by PCR, serology for antibody.

No treatment

Control with management (quarantine, disinfection, screening), and vaccine.

only prob is avian, control issue is aviaries
dx, tx, control of papillomavirus
Diagnose by characteristic lesions.

Human medicine – DNA hybridization to identify viral genome.

Usually regress on their own; surgical excision when needed.

Vaccine?
adenoviridae properties
Icosahedral nonenveloped virus.
- 80-100nm diameter
- 240 hexons (capsomers of the faces and edges).
- 12 pentons (vertices).
- Glycoprotein fibers protrude from each penton – responsible for attachment.

Linear dsDNA
- 30-38 kbp.
- 30-40 genes; ~1/3 encode structural proteins.
- Terminal protein covalently attached to 5’end; primes DNA synthesis.
- Histone-like proteins present
mastadendovirus
Mammalian viruses.

Many animal species including humans.

In people, causes colds, sore throat, upper respiratory infection, gastroenteritis, conjunctivitis; occasionally cystitis and hepatitis (infants).
atadenovirus
ruminant, fowl, possum, snake, other reptiles viruses.
aviadenovirus
Avian viruses.

Three groups:

I – many species of birds; causes hepatitis, bronchitis.

II – hemorrhagic enteritis, splenic disease in fowl (turkeys) – Now classified as separate genus: Siadenovirus

Egg drop syndrome – fowl; thin-, soft-, or no shell eggs.
- May be reclassified as Atadenovirus
adenovirus pentons
Toxic protein

If you take that from the virus and inject it in a cell, it will kill the cell

Interferes with cell membrane

Fibers attached to pentons
adenovirus attachment through replication
Attach via penton fibers.

Enters by endocytosis; endocytic membrane is ruptured by the pentons toxic activity.

Pentons and outer capsid removed

Core (consisting of genome and histones) migrates to nucleus, where uncoating, transcription (done by cellular protein) and replication occur
adenovirus early transcription
Done by host cell RNA polymerase.

Early proteins primarily nonstructural.
- E1A produced first – transcription activation, incl of cellular genes.
- Early proteins induce cell cycle progression (DNA synthesis), protect infected cell from immune response, and induce synthesis of proteins for DNA replication.

Functions of early proteins not completely understood.

Affect DNA replication, gene expression, host response; transformation.

E1A and E1B can transform cells.

E3 inhibits apoptosis by Tc Cells and downregulates MHC I expression.
describe what happens in early transcription of adenovirus

(in general terms)
Adenoviruses produce proteins in early phase to push cell into cell cycle so the cell will produce those enzymes that the virus needs to replicate

Produces things that interfere with interferon

Has the ability to start the ball rolling and make the cell grow due to the virus direction and if the cell isn’t killed (abortive virus) then the cell can continue growing out of control resulting in cancer
- Only seen in the lab so far, but vax controversial
adenovirus late transcription
Late transcription occurs after onset of DNA replication.

Late proteins primarily structural.

Uses newly synthesized DNA as template for late mRNA.

Complex control through promoters and feedback regulation.

Extensive splicing of mRNA.
only viruses that replicate _______ can undergo splicing
in the nucleus
how does the priming of transcription differ in adeno vs. parvo
In parvo, the DNA flipping back on itself is what primes transcription

In this, a protein product of early transcription is what primes the DNA
adenovirus

products of early transcription
Viral polymerase

Anti-interferon protein
adenovirus

DNA replication
Occurs after early transcription.

Requires viral DNA pol, DNA binding protein and terminal protein.

Host factors also required.

Proceeds by strand displacement.
- no lagging strands
- no okasaki fragments

Primed by 5’-linked terminal protein.

Proceeds from both ends
how is adenovirus deleterious to the host cell
Transcriptase is shifted from making host cell messages to viral messages
- It is creating viral parts not cell parts

causes cytolytic infections

Affects cell profoundly.
- Decreased cell protein synthesis.
- Inhibition of cell DNA synthesis.
- Toxic penton.
- Cell death.
adenovirus assembly in nucleus
Capsomers assembled, then capsid.

NA is packaged.

Core proteins added.

Accumulate in cell.

Released by lysis (no specific pathway for this lysis).
human adenoviridae dz syndroms
Respiratory disease
- Children – acute febrile pharyngitis.
- Childhood pneumonias
- Acute respiratory disease of military recruits

Conjunctivitis – “pink eye.”

Acute hemorrhagic cystitis (infants)

Gastroenteritis (less commonly – 24 hr bug)

Meningoencephalitis – rare.
1) are respiratory viruses usually enveloped or not?

2) enteric?
1) enveloped

2) non-enveloped
veterinary adenoviridae dz syndromes
Canine
- Infectious canine hepatitis.
- Upper respiratory tract disease (kennel cough).

Equine
- Upper respiratory tract dz
- Serious in immunocompromised foals – pneumonia.

Bovine
- Respiratory and enteric dz

Avian
how are adenoviridae spread
Spread primarily by fecal-oral spread; aerosol for respiratory forms; indirect spread via contact with contaminated objects (“fomites”).

Canine Adenovirus I spread by urine, persists for months in renal tissue.
- Impt b/c dogs smell each other’s urine
canine adenovirus 1
Infectious canine hepatitis.

Infects canids; also skunks, bears.

Entry through mucosal surfaces (nasal, oral, conjunctival).

Replicates at entry site in the epithelia and may spread to blood stream

Viremia follows.

Infects endothelial cells and parenchymal cells of many tissues, incl. liver.
- Usually in liver but can be in brain and other places b/c endothelial cells are everywhere
- encephalitis in foxes

Leads to necrosis.

Many infections asymptomatic; signs when appear include fever, depression, anorexia, vomiting, diarrhea, hemorrhages, and jaundice.

“Blue-eye” occurs during convalescence – due to immune complex formation; can also affect the kidney
what virus is associated with blue eye
canine adenovirus 1
canine adenovirus 2
Kennel cough

Replicates in respiratory tract epithelia.

Antigenically similar to CAV 1

Used in vaccine.

Upper resp tract
bovine adenovirus
Bovine, ovine, and caprine serotypes.

At least 9 serotypes of bovine adenovirus.

Virus replicates in epithelia of URT, LRT, conjunctiva, intestines.

Pneumonia in calves with fever, ocular and nasal discharge, dyspnea and cough.

Pneumoenteritis

Respiratory and enteric disease in calves.

Mainly resp disease
- Can go to lower resp tract
- Can survive transit in stomach and go to intestines but more common is resp disease
equine adenovirus
Aerosol spread.

Most infections are self-limiting and asymptomatic.

May present as mild respiratory tract disease with fever, nasal discharge, and cough.

In immunocompromised foals, infection is progressive, leading to pneumonia and death.

See in Arab foals with SCID.

Widespread destruction of epithelial cells.
group 1 aviadenovirus
conventional agents

Chickens, quail, ducks, pigeons.

Inclusion body hepatitis.
- Usually seen in broilers, 3-7 weeks of age.
- Significant mortality

Quail bronchitis.
- Respiratory distress, cough, sneezing, ocular discharge.
- Mortality 100% in young birds
- Highly contagious, spreads rapidly.
group II adenovirus (siadenovirus)
Hemorrhagic enteritis of turkeys.
- Turkeys older than 4 weeks of age; ~6-12 weeks.
- Splenomegaly, intestinal hemorrhage.
- Depression, bloody droppings; immunosuppression occurs.
- May have significant mortality in affected flocks – up to 60%.

Marble spleen disease of pheasants.
- Despite its name, causes acute respiratory disease.
- Seen in birds over 3 months of age.
- Pulmonary edema leads to asphyxiation.

Both siadenoviruses have characteristic splenic lesions.

Viral-induced anaphylactic reaction.
what virus is associated with egg drop syndrome
atadenovirus
atadenovirus
egg drop syndrome

Layers, other fowl, wild and domestic.

Virus replicates in oviduct leading to necrosis of epithelial cells.

Thin-shelled, soft-shelled, or shell-less eggs.

Transmitted via eggs and droppings.
adenovirus dx, tx, control
Diagnose by serology, virus identification using virus isolation or antigen detection assays. PCR becoming more widely available.

Treatment is supportive.

Vaccines routinely used for canine adenovirus – uses CAV-2 to avoid “blue eye”.

Human adenovirus not routinely vax for due to concern over oncogenesis; vaccine used in military recruits at high risk.