influenza and other enveloped viruses Flashcards
characteristics of enveloped viruses
1: a nucleocapsid coated with a lipoprotein membrane
2: infectivity destroyed by treatment with ether
3: unstable so transmission requires close contact
4: more complicated pattern of assembly than that on nonenveloped
5: few cell-associated virions at any time
6: continuous release of virions without gross cellular damage
7: modified cellular membrane containing glycoproteins within the envelope membrane
8: released from infected cells by budding
9: antigens for neutralizing antibody are envelope glycoproteins
envelope
What are the features of viral envelopes… What are they composed of?
Can enveloped viruses be neutralized?
Are they sensitive to ether?
Are they stable?
Are infected cells killed? How does the virus leave the cell?
composed of lipid molecules and viral glycoprotein spikes
neuraminidase and hemagglutinin
antibodies can’t neutralize because can’t get to capsid - target antigens are on envelope
makes viruses sensitive to ether - can’t bind to cells anymore because will dissolve the envelope
enveloped viruses usually unstable extracelluarly
virus doesn’t have to kill cell to get out of it - just buds out
classes of enveloped viruses
paramyxo- herpes- toga- flavi- rhabdo- orthomyxo- hepadna- retro- pox-
budding of enveloped viruses
viral caspid attaches to transmembrane receptors on host plasma membrane - these receptors were made using viral genetic material
this membrane surrounds the viral caspid and buds off
orthomyxoviruses genetic material
aka influenza virus A, B, C
What is the structure of nucleotide?
Plus or minus strand?
contain 8 separate segments of single-stranded RNA - each segment has the genetic information to encode at least one unique viral protein
each RNA segment enclosed in separate helical nucleocapsid
RNA cannot function as mRNA because is minus strand
virion contains virus-specific RNA polymerase - makes mRNA from virion (-)-stranded RNA
replication cycle of influenza virus
1: attaches to cell membrane
2: endocytosis and acidification
3: fuses with endosome/lysosome membrane and releases genetic material into cell
4: genetic material moves to nucleus
5: converted to mRNA and translated
6: translated proteins move back to nucleus and others are post-translationally processed and inserted into the host cell plasma membrane
7: genetic material is moved from nucleus to cytoplasm and packaged in host cell membrane where the viral proteins have been inserted
buds off and is released
classes of viral antigens (2)
1: nucelocapsid proteins
2: envelope glycoproteins
nucleocaspid
How many nucleocapsids do orthomyxoviruses aka flu virus have?
Do antibodies to nucleocapsids have effect in enveloped viruses?
structure composed of caspid proteins and nucleic acid genome
antigens located on protein capsomers of helical nucleocapsids inside virion
orthomyxoviruses have eight separate helical nucleocapsids
antibodies to nucelocaspid proteins don’t neutralize virions because don’t penetrate past the envelope around the virions
caspid proteins
What are?
protein coat that covers the nucleic acid genome
envelope glycoproteins
What are the two envelope glycoproteins that are antigens?
hemagglutinin and the enzyme neuraminidase
hemagglutinin (H or HA)
What does this glycoprotein do for the virus?
How effective are antibodies to this envelope protein?
required for adsorption of virions to cells - required for infection of susceptible cells
antibodies directed against it will neutralize orthomyxovirus virion - these antibodies are most important in controlling infection
binds to sialic acid molecules on host cells
neuraminidase (N)
What does this enzyme do for the virus?
enzyme that releases newly formed virions from their final point of attachment to the infected host cell by cutting sialic acid bonds
antibody to it slows release of newly formed virions and spread of infection to other individuals, reduces severity of disease but does not block infection of new cells or neutralize virions
hemagglutination
What is?
What virus is this diagnostic for?
Does agglutination test for the whole virion?
process by which orthomyxoviruses agglutinate red cells
used to measure relative concentration of virions in a clinical sample
does not require that the virions be infectious - only that H-antigen present
since specific antiviral antibody directed against H-antigen inhibits hemagglutination can be used to titrate the relative concentration of antiviral antibodies in serum samples - if antibody present won’t get glutination - RBCs will clump
when virus present, RBCs won’t form clump at bottom of test tube - form sheet so still clump, but it looks clearish/light pink and is spread out
influenza epidemics
What is the definition of an epidemic?
pandemic (world-wide epidemic) of 1918-1919 caused millions of deaths (30-50 million)
epidemic detected/determined by calculation of how many people die over what’s expected for that disease
types of influenza virus
three types: A, B, and C
each has its own specific nucleocapsid antigen (one for A, B, and C - called the S-antigen)
multiple strains of each type based on antigenic differences in hemagglutinin and neuraminidase and genetic variation in polymerase genes and other genes
influenza type B epidemics
How often do these occur?
What do the vaccines include?
occur every 3-6 years
vaccine usually contains one B strain that’s anticipated to represent the predominant H-antigen and N-antigen types for the future flu season
killed flu vaccine contents
Why are killed flu vaccines suboptimal?
vaccine usually contains one B strain and two A strains that are anticipated to represent the predominant H-antigen and N-antigen types for the future flu season
influenza type C has minor clinical significance
formaldehyde killed
injected
new virus isolates added each year
more than 70% effective when vaccine is well-matched to predominant viruses
suboptimal in protection because does not efficiently induce secreted IgA - primarily induces IgG response and IgG antibodies
recommended for everyone over the age of 6 months, special risk groups, and medical personnel
about 65% effective - but likely to be less severe illness if vaccinated even if you do get sick
live flu vaccine contents
What are the benefits?
What age groups are recommended?
approved in 2012
has two influenza A and two B strains or several of each
administered by intra-nasal spray
selected for optimal growth at low temperature - so ideal for upper respiratory tract and nasal cavity but does’t grow well deeper in the respiratory tract
approved for use in ages 2-49
may give 30-50% greater efficacy than killed (at least in preschool-age children)
get more IgA response with this than with the killed vaccine
epidemics of influenza type A
How often do epidemics occur? Minor? Major?
minor epidemics occur every 2-3 years
major ones every 10-30 years
antigenic drift
Which flu antigen is affected?
Do prior antibodies provide any protec
explanation for minor epidemics
minor variation within existing RNA segments in the gene for H-antigen due to mistakes made by viral RNA polymerase, spontaneous mutations, and other mechanisms
results in different minor antigenic variant of H-antigen
existing antibody from previous epidemics confers partial immunity
antigenic shift
Which antigens shift?
What are possible causes?
explanation for major pandemics
happens when existing antibody from previous epidemics fails to confer immunity
result of major antigenic variation
strains of influenza A can have same N glycoprotein antigen, but the H glycoprotein antigen is always antigenically shifted (sometimes both shift - results in worse pandemic)
major mechanism = introduction of a major H-antigen variant directly from swine or avian influenza A - this genetic reassortment between species is frequent because the viral genome is segmented
can also occur by direct transmission of a animal flu to humans, though less likely to cause an instant pandemic because would be unlikely to propagate well in humans but if minor mutations accumulate the virus may become well adapted to humans and cause a pandemic
influenza (disease characteristics)
How is it diagnosed in the lab?
What is transmission?
What cells in the respiratory tract are damaged by flu?
What affect does that have on other infectious agents?
subclinical infections common
laboratory diagnosis by virus isolation in embryonated eggs or tissue cultures or by comparison of acute and convalescent sera (anti-HA assay or hemagglutination inhibition assay)
transmitted person to person by coughs and sneezes
droplets initially infect upper respiratory tract then extend to lower
infects ciliated cells best - damages cilia
increases risk of other infections.
influenza (pathogenesis)
Is viremia involved?
fever, chills, aches
destruction of ciliated epithelium in respiratory tract
viremia not common
systemic symptoms (headache, muscle pains) caused by pro-inflammatory mediators released from sites of local growth in the respiratory tract
in severe cases contributes to lung disease
most common complication = pneumonia
pneumonia
From what virus is this a common complication from?
most common complication due to influenza
sometimes with secondary bacterial infection from pneumococcus or staphylococcus - occurs because of destroyed ciliated epithelium and malfunctioning infected alveolar macrophages
deaths due to influenza
Why did the 1918-1919 flu kill 20 to 40 year olds more than other age groups?
deaths usually occur in elderly and infants (though in the 1918-1919 pandemic deaths in very young and people very old but mostly in people from 20ish to 40ish)
death usually due to underlying respiratory insufficiency
20 to 40 year olds were killed do to immune response to flu (they had a stronger immune response than other age groups.
immunity to influenza
no obligatory viremia so incubation period short (days)
attacks mucosal surface of respiratory tract so immunity largely dependent on IgA
immunity may only be short term (3-10 years)
treatment of influenza
What drugs are used to treat?
What is their mechanism?
When does treatment need to be employed to be effective?
drugs = oseltamivir (tamiflu) and zanamivir (relenza)
both neuraminidase inhibitors - prevent neuraminidase from cleaving sialic acids on particles, which would allow them to be released - if cleavage is prevented, the newly budded virus remains stuck on the host cell
active against A and B viruses
slows release of virus from infected cells and slows spread from cell to cell
reduce symptomatic period by a day or two
only effective if treated early in infection period though
some H1N1 strains have resistance to tamiflu, others resistant to relenza
amantadine
Why is this drug no longer used?
older family of anti-influenza drugs
no longer really used because most type A flu strains have acquired immunity to it and it doesn’t treat type B
but still inhibits H1N1
tricyclic amine that likely blocks late phase of adsorption-penetration-uncoating process - mechanism not established
more effective if given before infection
paramyxovirus genetic material
What kind of nucleotide? positive or neg?
Can recombination occur?
one piece of single-stranded RNA within helical nucleocapsid - therefore recombination by reassortment can’t occur and marked antigenic variation not observed
negative stranded
information first transcribed into mRNA by polymerase present in the virion
paramyxoviruses of humans
what are the four kinds of?
one kind has for subtypes 1-4
mumps, measles, four types of parainfluenza virus (1-4) and respiratory syncytial virus (RSV)
non-systemic paramyxoviruses
What are the two?
What are their clinical outcomes?
What age groups are affecte?
Does agglutination test work?
the parainfluenza viruses and RSV
have no major shifts in antigenicity
many subclinical infections
severe, febrile, lower respiratory infection only in initial (childhood) infection
infection doesn’t result in life-long immunity so adult infections common
virons agglutinate RBCs so hemagglutination tests useful
Croup
What virus causes this disease?
What are the symptoms?
What age groups are primarily affected?
What is the treatment?
acute laryngo-tracheo-bronchitis
characterized by dyspnea and stridor (high-pitched noisy inspriation)
primarily occurs in children up to age 3, peak at age 2
parainfluenza viruses are most common cause
treat severe cases with glucocorticoids (to reduce inflammatory response)
respiratory syncytial virus
What disease does it cause?
What is the treatment and efficacy?
What age group is affected?
What treatment is given to high risk infants?
most frequent cause of severe lower respiratory infection in infants and significant infection in elderly
treat with ribavirin aerosol but of uncertain efficacy so used only in high-risk patients
adult infections common because IgA doesn’t provide good long-term immunity
can use very high dose of monoclonal antibody against RSV to give passive immunization to high risk infants
also treat with aerosolized ribavirin
SARS (severe acute respiratory syndrome)
What virus causes this disease?
What are the principle symptoms?
What age group is affected?
What is the fatality?
lower respiratory tract infection caused by coronavirus
principle symptoms = dry cough and dyspnea
almost always in adults
severity increases with age
case-fatality rate about 9%
coronavirus
Envelope status? Nucleotide status? incubation period? transmission? symptoms?
enveloped with helical nucleocapsid
single molecule genome of plus-stranded RNA
cause of common cold and SARS (but different strains)
incubation period = 2-10 days
can be transmitted by respiratory droplets
dry cough and difficulty breathing
interferon system
What are the two proteins?
Does it have viral specificity?
How long does this treatment/physiological resistance last?
system functions to suppress viral growth
consists of two classes of proteins: interferons and virus inhibitory proteins
both types newly synthesized after viral infection
does not have viral specificity, though may be more effective in response to some viruses than others
transient production of these proteins (as opposed to IgG, which is made for life, and IgM which takes a few months to decline)
interferon proteins
How do these work against virus?
proteins newly synthesized and secreted into the extracellular fluid by virus-infected cells (alpha and beta interferons) and by antigen-stimulated T-cells (gamma interferon)
acts to block protein synthesis - as a result infected cells can’t produce progeny virions
virus inhibitory proteins
What is the mechanism against virus?
proteins synthesized by uninfected cells when their plasma membrane interferon receptors bind interferon molecules
examples: 2-5-A synthase and protein kinase R (PKR)
acts to block protein synthesis - as a result infected cells can’t produce progeny virions
proteins inactive until interferon-treated cell becomes infected and are activated by double-stranded RNA so non-toxic to uninfected cells
activation of interferon response to viral infection
triggered by recognition of infection by pattern recognition receptors like toll-like receptors
can also be triggered when cytoplasmic RIG or MDA proteins recognize viral RNA - induces interferon gene expression
2-5-A synthase
What is this?
What does it do?
type of virus inhibitory protein - part of interferon response to infection
synthesizes 2-5-A = short polynucleotide that has adenosines linked by a 2’ to 5’ phosphodiester
this activates a ribonuclease that destroys mRNA - prevents protein synthesis
protein kinase R
What is this?
What does it do?
type of virus inhibitory protein - part of interferon response to infection
phosphorylates initiation factor 2
initiation factor 2 is needed for the start of protein synthesis, phosphorylation inactivates it
influenza genetic material
Explain the genetic diversity of?
has 8 separate pieces each individually wrapped in its own nuclear proteins
important because multipart virus so can recombine strains which allows for wide genetic variability and also for exchange of RNA segments between human viruses and other mammal viruses, especially birds and pigs - rare event cause to replicate well in birds probably doesn’t replicate well in humans but likely what happened for spanish flu epidemic (of 1918)
negative sense RNA
must make a copy of itself to make mRNA and therefore to make proteins
cellular enzymes don’t have anything that can copy RNA to another RNA so virus brings RNA-RNA polymerase
interferon alpha
What is this?
What does it do?
will bind to neighboring, uninfected cells - makes cell more inhospitable for viral infection - get induction of 2’5’oligo A synthase => production of 2’5’oliogo A - this then induces ribonuclease L => degradation of mRNA
also get induction of protein kinase = inhibition of protein synthesis (because protein kinase is activated and eIF-2 is phosphorylated)
What is the difference in nucleic acid structure of orthomyxo vs paramyxo viruses?
former is neg ssRNA with 8 separate strands
latter is neg ssRNA with one strand
