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Influenza Pathogenicity Factors (Haemagglutinin Receptor Preference (Pigs,…
Influenza Pathogenicity Factors
Haemagglutinin Receptor Preference
HA binds salic acid
Salic acid is a terminal sugar on carbohydrates
It has different linkage confirmations
Some influenza strains have affinity for both
α2,6 Linkage
Human influenza predominately binds
Salic acid in this conformation is usually found in the human upper airway
α2,3 Linkage
Avian influenza predominantly binds this SA
Salic acid of this type is found in the lower airway
Zoonotic H5N1 could bind both α2,6 and α2,3
Pigs
Immunofluorescence imaging has shown that pigs have both α2,3 and α2,6 SA receptors
Therefore can become infected with both human and avian viruses
If occurs at the same times then may get reassortment
The differences in the distributions of α2,6 and α2,3 receptors are thought to be why avian viruses are less pathogenic in humans. They can't est. an infection in lungs.
Some avian Influenzas have specificity for both.
Infers at a transition between a preference for the gut to the resp tract
Tissue Target Range
HA Background
Produced as a monomer
Then becomes a trimer
The cleaved to liberate HA1 and HA2
HA2 has main fusion peptide
Cleaved by tryptase clara
Only in resp tract
Therefore the virus can't replicate elsewhere
Protein undergoes conformational change once bound to the cell surface
Probably due to pH of endosome (acid)
Low to High Pathogenicity
Addition of 3 basic amino acids before cleavage site
Become more pathogenic
Can now be recognised by most proteases
As these proteases can recognise the now
polybasic
cleavage site
1918 however
doens't
have polybasic site
These poly basic sites are thought to be the major mortality cause in poultry
Neuraminidase is thought to help with the cleavage of HA
The 1918 is thought to have been made more pathogenic by this method
Replication & Release
Polymerase Activity
Works best at different temperatures
Respiratory Tract 33ºC
Lungs 40ºC
Has to undergo changes in AA sequence to adapt for optimum replication in the two
Need a change in PB2 single AA change to get this adaption
Neuraminidase
Change in structure between gut and resp viruses
There's an increase in acid stability in gut viruses
'Stalk' is shorter in the gut
Host response
NS1
Non-structural
Reverses host IFN response
Innate response linked to pathogenicity
r1918 is more effective at blocking the IFN response and its subsequent linked genes than a WSN seasonal strain
Were experiments to show this
r1918 repressed IFN and didn't give induction
r1918 also downplays lipid metabolism
Needed in IFN production
PDZ
Virus ligand binds PDZ domains
Some ligands found exclusively in human strains others in animals
Shows an evolutionary change from A :arrow_right: H
r1918 had exclusively human ligand
The identity of PDZ NS1 ligand alters pathogenicity
1950 H1N1 (WSN) gave a lower P50
RSKV has lower PDZ affinity
ESEV (avian) has a higher PDZ affinity
PB1-F2
Variable length peptide
A serine at position 66 (S66) gives a high patghogenicity
Binds to MAVS and inhibits MAVS-mediated IRN
Through this apoptosis can be activated
2009 H1N1
Had α2,6 preference as well as slight α2,3
Truncated NS1
Infer less pathogenic
PB1-F2 Truncated
Host restriction factor IFITM-3
Variants are linked to severe influenza