Influenza epideomology and pathogenesis Flashcards
Influenza variation is mostly determined by what segment
HA
Infleunza virus isolates (new) are named using several different criteria: what are the 5
- Subtype (a/b/c)
- Location of first isolation
- Number of isolations
- Year of first isolation
- Information on HA and NA proteins.
HA proteins are divided into how many groups
17/18
How are different HA and NAs distinguished
Distinguished on the basis of reactivity with a panel of antibodies.
How many HAs and NAs are there
Currently 18 HAs and 9 NAs.
What type of animal can all type A influenzas infect
Birds
What enzyme most commonly cleaves HA0
Human airway trypsin (HAT)
Can some HA proteins attatch to both SA linkages
Yes
H1-3 have a high affinity for what SA linkage
Have highest affinity for alpha2-3 SA but also good affinity for alpha2-6
Low pathogenicity flu strains tend to have what HA groups
H1, H2, H3
What are HPAI viruse strains
H5 and H7
HPAI stands for
highly pathogenic avian influenza viruses
In humans what makes H5 and H7 strains dangerous
In human H5 and H7 strains are not restricted to the respiratory tract and can infect other cell types.
Different NAs release to ability to what
cleave the host’s sialic acids during virus release.
How is the virus transmitted
Virus inhalation via RT
Direct contact of fomites
What is a typical outcome of influenza virus infection
Tracheobronchitis with some involvement of small airways.
Symptom progressio time line
Rapid onsent- 24hrs post contact
Virus replication titre peat 48hr post infection
Symptoms peak at day 3
Initialy symptoms d1-d3
Headache
Fever
Dry cough
Sore throat
Muscle aches
Tiredness
Later symptoms d4-d8
Rhinitis
Sneezing
Productive cough
Complications of influenza infection
- Viral pneumonia- more at risk are the old and smokers
- Cardiac involvement
- CNS involvement
What are the optimal conditions for transmission
Transmission best at 5C and 20-35 (low) humidity.
Who found to Spanish flu strain in Alaska
Johan Hultin
When the Spanish flu virus was sequenced what strain was it
H1N1
1918 flu virus had a HA which could be cleaved by what proteases
The 1918 flu virus had HA that could be cleaved by other proteases found within many cell types like Furin or PC6 or no exogenous protease at all. The virus could go systemic.
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What determines what proteases can cleave HA0
The amino acid sequence of the site determines which proteases can cleave it
How many basic residues mean airway/gut trypsin can only cleave HA0
One basic residues – cleaved by airway/gut trypsins only – disease restricted. Mono-basic
cleavage site
How many basic residues mean multiple proteases can cleave HA0
Multiple basic residues – cleaved by multiple proteases – systemic spread. Multibasic cleavage site.
What is the HA0 cleavege site near to
Fusion peptide
What is antigenic drift,
Single nt changes during RdRp mistakes during copying
Due to the 1/10000nt error rate and the flu genome being 10,0000nts, what is created?
Quasi-species
where do most drift changes occur
HA1, outside the receptor binding site
When does antigenic shift occur
When segments mix within a cell
What anumal often allows human and avian strains to mix. Why?
Pig. Pigs have both a2-3 and a2-6 linkages
H1N1 (current) as an example of antigenic shift: what mix of viruses is it
- Initial triple event occurred between avian (North American avian), swine (classical swine) and human viruses (H3N2).
- A second reassortment event with Eurasian avian like swine occurred.
What are the three requiremements for human-human spreas
- Ability to enter cells of human URT
- Ability to replicate to high number in URT cells
- The ability to exit cells of the URT.
- Current H5N1 avian influenza strains cannot do any of these things very well.
H5N1 human infections have what HA change
Q222L, G224S
What requirement is H5N1 infleunza mising
Ability to enter cells of URT
GISRS stands for
Global Influenza Surveillance Response System
What is the traditional method of flu vaccine production
3 strains weakeneded, segment exchange with weak PR8 –> reassortment
Issues with traditional way of producing flu vaccines
- Generation and selection of 3 reassortments is slow of 3 months- from selection to product is a minimum of 9-10months.
- Dependence on egg production: need 170 million eggs
- Some H5N1 viruses growl poorly in eggs.
Traditional vax: The seed strain infects what
Eggs
What is the new way of producing influenza vaccines
There is generation of reassortment flu viruses from cDNAs
There are 8 cDNAs encoding RNA genome sequences.
What is Flucelvax
cDNA based production of vaccine
What are the three targets for anti-influenza therapeutics
- Endosome escape
- RNA synthesis
- Release
How do Adamantanes work?
Prevent M2 ion channel activity, binding will block pore to prevents passage of H+ so the matrix layer remains intact as the pH doesn’t drop and so virus cannot exit the endosome.
Pros and cons of adamantanes
Pros: cheap and effective
Cons: Must be administered during early stages of infection (before 2 day)
Why are adamantanes no longer used
Most human influenza viruses are now resistant since 2003 where there was significant local strain resistance, in 2006 over half of human isolates of H3N2 influenza virus were resistant. In 2008 there was global resistance.
Resistance is conferred by virus mutations within the M2 channel itself. These prevent amantadine binding and blocking. No longer FDA approved to treat influenza.
How does Xofluza inhibit endonuclease activity
Rational design based on PA crystal structure.
Delivered as pro-drug BXM (Xofluza), FDA approved in 2018.
Drug binds the PA endonuclease active site, effective against broad range of influenza A and B viruses.
How many sites in the pocket are there between SA and NA
5 sites, S1-S5
What discovery lead to development of Relenza (zanamir) aerosol, Tamiflu (oseltamivir) oral tabley, Repivab (peramivir) IV.
A molecule that can out-compete SA for NA
