21. Influenza Flashcards
what is the structure of the influenza genome?
segmented negative sense RNA genome
what are the 3 influenza viruses?
influenza A
influenza B
influenza C
which is the most important influenza virus?
influenza A
why do the influenza vaccines need to be updated every year?
due to the antigenic drift of influenza
how can a significantly different influenza strain appear?
genetic reassortment called antigenic shift
these can evade all pro-existing immunity
What is commonly confused with influenza?
a bad cold but none are as bad as influenza
what are the symptoms of influenza?
headache
fever
cough
joint and muscle ache
fatigue
recover in about 2 weeks
who are the most vulnerable to influenza?
the very young and the very old
what commonly kills you when you have influenza?
a secondary bacterial pneumonia infection
how many influenza deaths are there in a typical year in the UK?
10,000-12,000
how many influenza deaths are there in an epidemic year in the UK?
20,000-30,000
how many people did the spanish flu kill?
over 40 million
more then WW1 and WW2 combined
how many genome segments does influenza have?
8 segments
how many proteins does influenza produce?
10 classical flu proteins
additional proteins produced by reassorment tricks
what are the components of the influenza virus particle?
membrane from infected cell
H protein
N protein
M1 matrix
M2 ion channel
genome segments
what are the influenza genome segments associated with?
3 virally coded replicated proteins
Nucleocaspid protein coating the length of RNA
what does the M2 ion channel do?
pumps H+ ions from outside the virus to inside
what are the H and N proteins
membrane glycoproteins - antigens
what does the M1 matrix protein do?
keep contact between the H and N glycoproteins and the genome protein complexes
How does influenza enter and infect the host cell?
- attaches to sialic acid residues by the H protein
- taken into an endosome which becomes acidified
- the drop in pH causes changes in the H protein and causes fusion of the virus and endosome membranes
- H+ enter the virion through M2 and causes RNA to be released and move to the nucleus
why is the H protein critical for endosomal membrane fusion?
drop in pH causes conformational changes in H protein that exposes sequences to attach to the endosome membrane
what is unusual about influenza as an RNA virus?
it replicates in the nucleus
what is each strand of the RNA genome associated with?
nucleocaspid proteins and replication proteins like RdRp
what does the RdRp make from the -ve sense ssRNA genome?
mRNA for transcription
a cRNA anti-genome for replication
where is all the coding information on a -ve sense ssRNA virus?
all the info is on the opposite strand including the start codon
how is the mRNA different from the anti-genome?
when making mRNA the RdRp detects a stop codon and poly adenylates the strand and other modifications
the cRNA anti-genome is a faithful copy of the genome
how does influenza generate more proteins then it has segments?
some influenza mRNA can be alternativly spliced which is why it must enter the nucleus
what carries out influenza mRNA alternative splicing?
the host cell’s splicing mechanisms
what happens when the new viral proteins appear on the cell membranes?
It makes them visible to the host immune system
what viral proteins are exported back to the host nucleus?
viral replication proteins to replicate the viral genome and export them to the new virions
what is the main influenza antigenic proteins the host recognises and produces antibodies to?
H (heamagglutanin)
what is the role of the influenza N protein?
destory the sialic acid in the host cell membrane so the virus doesn’t reinfect the same cell
how many know serotypes of H and N are there?
H = 15
N = 9
why do different influenza serotypes cause a problem for the host?
antibodies would only work against the same serotype so not much protection from reinfection
what causes antigenic drift?
occasional mistakes during genome replication and lack of proofreading
the viral progeny will have altered genes and some lead to changes on the H and N surface proteins
what can mutations in the genome do?
make the virus more effective and avoid the immune system
make the virus less effective or dead
what is the limitation of antigenic drift?
the virus structure needs to be able to tolerate alterations to its structure to able to survive the mutation
some viruses like measles cannot tolerate structural mutations
How does antigenic drift effect immunity?
some but not all of initially generated antibodies can recognise the strain
reducing the population immunity
what makes influenza vaccines useless after 4/5 years?
antigenic drift and the H protein’s ability to tolerate changes and be functional
these over a few years significantly reduce effectiveness
what other animals can influenza A infect?
horses
pigs
ferrets
birds
what is the mixing pot of influenza?
pigs
why are pigs the mixing pot for influenza A?
both human and bird influenza strains can infect pigs
how do influenza strains mix in pigs?
some cells in the pig will be infected with both the bird virus and the human virus
the compatible segments of the genomes can mix in the new virion particles
Doesn’t happen readily due to compatibility
what else can mix with the human and avian influenza strains?
native pig influenza strains
What is antigenic shift?
random genetic reassortments between the H and N genes on separate segments
what can influenza antigenic shift result in?
A virus that:
can infect and replicate well in humans
are antigenically different from other influenza that has been recently seen
what do antigenically shifted viruses usually result in?
a new epidemic/pandemic of influenza
what possibly was the 1890 flu pandemic?
a bovine coronavirus
what are the 2 alternate mixing pot ideas?
- an avian influenza adapts through zoonosis to infect humans
- the avian influenza and human influenza infect the same human at the same time and reassortment occurs
what usually limits avian influenza when jumping straight to humans?
they cannot sustain person to person spread
it is a worry that avian influenza could develop this and trigger a pandemic
what are the 3 routes influenza could take to become a pandemic strain?
- reassortment when an avian virus infects a person already infected with human influenza
- an intermediate animal (pig) could contract both at the same time
- an avian influenza might adapt through random mutation and acquire the ability to infect person to person
where are the 4 main WHO influenza monitoring labs?
london
atlanta, USA
tokyo
melbourne
what does WHO do when monitoring influenza?
recieve information about concerning strains
make yearly reports
Recommend strains to be included in the annual vaccine
what is the biggest limitation of the yearly influenza vaccine?
they have to decide what strains to included in march/april so they can be produced in time
it can be difficult to predict what the dominant strains will be
what are the 4 types of influenza vaccine?
inactivated virus (whole dead virus)
split vaccine (whole purified virus killed with detergents)
sununit vaccine (purified HA and N proteins)
Live attenuated influenza vaccine
how does the live attenuated influenza vaccine work?
the virus is modified to grow at the temperature of the nose and not the lungs
creates localised immunity and mucosal immunity
what is currently the most common influenza vaccine?
split vaccine
what is thought to be a good new influenza target?
M2 protein external region called M2e
why use M2e as a vaccine target?
- part of the H+pump
- M2e region hasnt changed since 1918
- shares gene with M1 so has very limited tolerance to mutation without knocking out both gene functions
- M2e appears on the host membrane earlier then other proteins
why have we not considered M2e as a target before?
the immune system doesn’t naturally make antibodies to it as only a small part is external
what do we need more understanding of to make better influenza vaccines?
- what parts of the virus rapidily change and what don’t
- what the body decides to make antibodies to and be able to manipulate it
what current treatment do we have for influenza?
Tamiflu
Relenza
(amantadine and flumadine)
how do current treatments for influenza work?
they inhibit different stages of the influenza replication cycle
what are the disadvantages for influenza treatments?
have to be given in the first 2 days of infection
side effects
resistance can emerge very fast
