Influenzaviruses Flashcards
What family do influenzaviruses belong to? How many strains are there?
Orthomyxoviridae family
3 Types of Influenza: A, B and C
- Within each type there are multiple subtypes
- All 3 can infect and cause symptoms in humans, but pandemics caused solely by Type A
- Infection with one type or subtype does not confer immunity to another type of influenza
Which type of influenza is the cause of of major outbreaks throughout history?
Influenza Type A
What is the following of Influenza Type A:
- Host Range
- Epidemiology
- Clinical Features
- Genome
- Structure
- Host Range: Humans, pigs, horses, birds,
- Epidemiology: Antigenic Shift and Drift
- Clinical Features: May cause pandemics (esp. young ppl)
- Genome: 8 gene segments
- Structure: 10 viral proteins & M2 unique
What is the following of Influenza Type B:
- Host Range
- Epidemiology
- Clinical Features
- Genome
- Structure
- Host Range: Humans only
- Epidemiology: Antigenic Drift only
- Clinical Features: Severe Disease; elderly, no pandemic
- Genome: 8 Gene Segments
- Structure: 11 viral proteins
What is the following of Influenza Type C:
- Host Range
- Epidemiology
- Clinical Features
- Genome
- Structure
- Host Range: Humans and Pigs
- Epidemiology: Antigenic Drift only
- Clinical Features: Mild disease, common in children
- Genome: 7 Gene Segments
- Structure: 9 viral proteins
What is Antigenic Shift?
hemaglutinnin protein
cell gets infected by two strains
the two strains can mix/match their RNA genomes called reassortment
produces hybrid viruses that ppl most likely don’t have immunity for
What is Antigenic Drift?
subtle changes/mutations in the hemaglutinin proteins
changes a little bit as it replicates
What is the difference between antigenic shift and drift?
Shift = etnirely new hemaglutinin (more dramatic = major change) Drift = subtle changes; slight mutation to hemaglutinin protein
How is virus nomenclature used to name viruses?
Influenza type (genus) Species isolated form (unless human) Place of Isolation Number of the isolate Year of isolation H and N subtypes (18 H and 11 N subtypes)
How would you name the 220th isolate of an H5N1 subtype virus isolated from chickens in Hong Kong is designated?
A/chicken/Hong Kong/220/97(H5N1)
What makes up the virion structure of influenzaviruses?
Envelope contains the H and N glycoproteins and M2 protein
Ribonucleoprotein complex (RNPs) make up the core of the virus. RNPs consist of
- viral RNAs complexed with the polymerase proteins
- PB1, PB2 and PA code for RDRP
How does influenza virus infect its host? (Attatchment/entry, uncoating, replication)
HA attaches virion to sialic acid residues on surface of host cell
virus enters through endocytosis
progressive acidifcation of endosome
- M2 ion channel allows protons into core of virus =
- Acidification = conformational change of hemaglutinin
- pokes hole in endosome
- allows release viral RNA segments
- endonucleus guides viral segments to nucleus
When viral RNA segments get into the host nucleus:
- (-) RNA segments have to be transcribed to (+) RNA -
- (RDRP = PB1, PB2, PA segments)
- cell ribosomes can recognize the (+) RNA and produce viral proteins
What are the functions of the following influenzavirus proteins that make up the ribonucleoprotein complex?
PB1, PB2, PA = RNA Dependent RNA Polymerase
HA = Hemaglutinin binds sialic acid residues on surface of host cell for attachment
NA = Neuraminidase cleaves sialic acid residues on surface of host cell for exit of new virions
M2 = ion channel that allows protons to enter virion and causes conformational change to hemaglutinin that results in release of viral segments into host cytoplasm
What is the influenzavirus lifecycle?
- Attachment to sialic acid
- Endocytic entry
- Uncoating and release of vRNPs into cytoplasm
- Translocation of vRNPs into nucleus
- Generation of mRNA and positive (+) strands and more (–) strand RNA genomes
- Production of viral proteins
- Genomes packaged into pre-assembled capsids
- Budding and release of progeny virions
What are the characteristics that influence influenzavirus attachment?
Hemagglutinin Binding to sialic acid linked to galactose on cell surface
Human viruses bind α2,6 Galactose (in respiratory tract)
Avian viruses bind α2,3 Galactose (in bird intestines)
Difference influences pathogenesis in these two species
What change in binding specificity made the spanish flu so deadly?
Current work suggests that a single amino acid change within the HA of Spanish flu (1918 pandemic) resulted in the ability of this avian flu virus to now bind α2,6 Galactose
Normal avian viruses bind α2,3 Galactose
Go over the uncoating step for influenzaviruses.
M2 ion channel in the viral envelope allows H+ ions to penetrate the virion
Weakens the viral M1 matrix protein from the vRNPs
vRNPs released into the cytoplasm
What drugs block the uncoating step in influenzaviruses?
Amantidine (sold as Symmetrel) and rimantidine (sold as Flumadine) block the M2 ion channel function, interfering with uncoating.
What do influenzaviruses have to do in order to replicate? What about making viral proteins?
Replication
- have to make (+) RNA antigenome
- template to make more (-) ssRNA influenzaviruses
Viral Proteins
- (+) RNA antigenome is used to translate viral proteins using host ribosomes
How are influenza virions released from host cell?
Virions are released by budding
The viral NA protein cleaves the sialic acid on host cells to prevent clumping of viral particles at the host surface.
What drugs interrupt virion release of influenza viruses?
Zamanivir (sold as Relenza) and oseltamivir phosphate (sold as Tamiflu) inhibit the function of NA.
Go over the pathogenesis of influenzaviruses.
droplet transmission
Virus enters respiratory tract
Attaches to ciliated columnar epithelial cells lining the sinuses and airways
Primary site of infection—tracheobronchial tree, involving nasopharynx
As virus replicates, cilia are destroyed
- Cleaning system in the lungs does not work as well
- mucus stays in the airway causing coughing
- Virus replication peaks at 48 hours and then declines
- Virus shed for up to a week
Destruction of cilia contribute to secondary bacterial pneumonia infections, sinusitis, otitis
What is the incubation period for influenza? Who are the carriers? How is it transmitted?
Influenza has a short INCUBATION PERIOD within the host
- Infection to symptoms is approximately 1 to 2 days
Infected individuals act as ACUTE CARRIERS of the disease
Infected individuals readily TRANSMIT the virus by coming
into contact with un-infected individuals or by expelling the virus into the environment in the form of FOMITES
What are the clinical features of an uncomplicated infection from influenza?
Onset of symptoms: Headache Aching in the limbs and back Fever (100-103oF) Malaise Dry cough Sore throat Chest X-ray is normal
Usually resolves itself after 7 days
What are the clinical features of an complicated infection from influenza?
Age-dependent
Young children—croup, secondary bacterial pneumonia, middle ear infections
Elderly—life threatening secondary bacterial pneumonia, pre-existing conditions like congestive heart disease exacerbated
Immune compromised individuals—at risk of death during an influenza epidemic
How do you develop immunity for influenzaviruses?
Infected individuals develop antibodies against the outer proteins of Influenza virus—neuraminidase (NA) and hemagglutinin (HA)
Antibodies against HA neutralize the virus
Antibodies against NA do not but they do reduce the release of virus from infected cells
What composes the trivalent influenza vaccine?
Recommendations made based on antigenic analyses of recently isolated influenza viruses, epidemiologic data and post-vaccination serologic studies in humans
Vaccine is a cocktail of 3 virus strains
- 2 strains of Influenza A
- 1 Influenza B strain
What determines effectiveness of influenza vaccine?
Age of the vaccine recipient
Immunocompetence of the recipient
Degree of similarity between the viruses in the vaccine and those in circulation
What are the antivirals used for influenza?
First drugs: M2 inhibitors (prevent uncoating step)
- Amantidine (sold as Symmetrel)
- Rimantidine (sold as Flumadine)
New class of antivirals: NA inhibitors (prevents neuraminidase from cleaving sialic acid during budding)
- Cause viruses to clump at cell surface, reduce viral spread
- Oseltamivir (sold as Tamiflu, pill form)
- Zanamivir (sold as Relenza, must be inhaled)
What is the mechanism for generation of new pandemic influenza Type A viruses?
Reassortment
What was significant about the mortality rates for the spanish flu when compared to regular flu?
Spanish flu had a W shaped mortality curve instead of a U shaped curve
Killed 20-40 y/o’s more than regular flu
What were the researchers trying to accomplish in this study? What was their hypothesis? What were their goals?
BIRD FLU PAPER
Find out what changes need to occur to this bird flu strain to make easier to transmit from person to person (possible pandemic).
This bird flu is highly virulent but low transmissibility. Is it possible to mutate virus so that it can spread via aerosol route. Thought they could mutate it by changing the HA.
How did the researchers carry out their study? What methods did they employ to accomplish their research objectives.
BIRD FLU PAPER
First made changes in viral protein that binds receptor (hemaglutinin - sialic acid).
- Thought this would increase transmissibility b/c they wanted to change it from alpha-2-3 sialic acid (binds birds better) to alpha-2-6 sialic acid (binds humans easier)
Initial change did not make it more transmissible.
Second, they serially passaged the virus through ferrets (infect 1 group, take out infect 2nd group etc) to allow the virus to evolve with each replication. Hoping to see mutations as result of viral replication.
Why did they choose the A/Indonesia/5/2005 (H5N1) strain for this study?
BIRD FLU PAPER
highly virulent. incidence of human A/H5N1 virus infections and fatalities in Indonesia remains fairly high
concerns this virus could mutate to increase transmissibility between humans and cause a pandemic.
Why did they choose ferrets as their animal model?
BIRD FLU PAPER
Susceptible to infection with human and avian influenza viruses
Develop respiratory disease and lung pathology similar to that observed in humans
Ferrets can also transmit human influenza viruses to other ferrets that serve as sentinels with or without direct contact.
Describe the main findings of the paper.
BIRD FLU PAPER
After passaging virus 10 times they noticed they had 4 mutations to HA in addition to their original change they did themselves
- The other mutation was on PB2 (one of the genes needed for RDRP)
They observed that the virus could become airborne transmissible
Also the mutations that brought on airborne transmission also mutated the virus to become less virulent too.
What are some of the scientific and societal implications of this work?
BIRD FLU PAPER
The mutations that arose in this SINGLE strain arose through antigenic drift (usually pandemics arise through antigenic shift) so you can get pandemic strains through antigenic drift too.
