Influenza

How does the budding site of influenza effect whether it establishes local or systemic infection?

• Buds from apical surface of respiratory epithelial cells

• Released to respiratory tract, assisting local spread

• Greater chance of establishing systemic would be to bud from basal layer (to access blood) , which it doesn’t do

Compare influenza to poxvirus immune evasion

• NS1 targets many different pathways vs at least 14 different proteins e.g. A49 for NFkB and IFN signaling, suicide substrate CrmA

What is significant about influenza’s NS1

• NS1-knockout viruses do not induce an interferon response and are much less lethal (in mice)

• Tackles multiple intracelllar innate immune pathways at once including interferon production, apoptosis and inflammasome production

• One viral protein, many host binding sites that be inhibited

Basic influenza facts

• -ssRNA with 8 segments

• Helical nucleocapsid

• Envelope containing HA, NA, M2 etc.

• Replicates in the nucleus

• 18 HA, 11 NA

Describe how influenza regulates the fusion of th viral and endosomal membrane and why this is useful

• Fusion peptide of HA2 is hidden at physiological conditions

• Acidification by the endosome causes conformational change of HA that reveals HA2 FP

• Regulates when M2 inserted into endosome membrane

• Can begin importing H+, regulating -ssRNA release from nucleocapsid into cytoplasm

Why does influenza colonise the cells that it does, if sialic acid is present everywhere?

• Cannot survive outside the cell for long

• Nearest entry site is respiratory epithelium as transmitted through inhaled droplets

Fully describe how the influenza genome is replicated

• Viral RdRp transcribes each -ssRNA segment to mRNA in nucleus

• Cap snatching from endogenous mRNA so host ribosomes eIFs can assemble and translate

• Some does not get modified and remains as cRNA to be packaged in the genome

In general, each influenza -ssRNA segment codes for one protein, but segments 7 and 8 can be spliced to produce…

• M1/2 and NSP1/2

Fully describe the assembly and release of influenza

• Buds through the membrane, acquiring host envelope

• Virus proteins required in envelope are transported independently to the new plasma membrane

• NA cleaves sialic acid residues from host cell and HA1

Antigenic drift vs antigenic shift

• Drift when individual amino acid changes within the HA epitope due to low fidelity polymerases decrease the recognition of HA epitope by nAb CDR, so selection for those with mutations that can no longer be detected

• Shift is radical change in genome due to reassortment of RNA segments during co-infection of the same cell by 2 different influenza viruses, leading to a new HA

What is the worst combination of antigenic shift in influenza and give an example

• 7 segments from human, one segment (seg 4, the HA) from avian

• Progeny replicates well in humans but completely evades immunity

What is significant about influenza’s NS1

• NS1-knockout viruses do not induce an interferon response and are much less lethal (in mice)

• Tackles multiple intracelllar innate immune pathways at once including interferon production, apoptosis and inflammasome production

• One viral protein, many host binding sites that be inhibited

What are three anti-influenza agents and simply, what do they target?

• Amantadine and rimantidine block M2 of influenza to prevent acidification of endosome and viral entry in to the cell

• Tamiflu is sialic acid analogue so binds NA, prevents cleavage of sialic acid from HA1 so cannot bind new host cells and causes aggregation of virions

Capsid shape of influenza

• Helical