Influenza lecture 1

It is one of only a few pathogens that has the potential to decimate the human populations

• Most strains cause mild disease with around 0.1% death rate 
• Some strains cause extraordinary diseaase with up to around 50% death rate

Seasonal flu is different from the common cold as it causes a fever. Most of the fatalities are in the elderly. 
The more serious strains are much rarer, generall not as easily transmissable.

Negative sense RNA molecule is non coding 
Positive sense RNA is coding 
THE FLU IS A NEGATIVE STRAND AND IS SEGMENTED
Segmented means that the genome is split into more than 1 molecule. 
The family name of flu is orthomyxoviridae
There are hundred of strains of flu A,B,C. A causes the most disease in humans 

Influenza virus A
- Initially an avian virus, adapted to grow in birds
- Infects: Humans, pigs, birds, horsesm aquatic mammals
- 8 segments
-Encoded 17 proteins 
- Causes severe diseases
- Causes global pandemics

Influenza virus B
- Infects humans only 
- 8 segments 
- Encodes 10+ proteins 
- Causes severe disease 
- No pandemic as yet

Influenza virus C
- Infect humans and pigs, has 7 segments 
- Encodes 10+ proteins
-Causes severe disease, but it is very rare
- No pandemic as yet

Pleomorphic virus particles, 80-120 nm in theta (virus particles are slightly different in shape despite being same species)
Occasionally rod-shaped elongated particles
Outer membrane derived from host cell 
3 membrane proteins 
- NA= Neuroaminadase- A tetramer with a pronounced head region 
- M2= A tetramer and fairly rare. Acts as an ion channel
- HA= Haemoglutanine is a trimer

Internal structures can be visualised in damaged virions or by tomography. 

Beneath membrane is a sheath of Matrix (M) protein 
The virus interior includes 8 RNA segments
- Matrix proteins associates with end or spikes as they fit through envelope. Can also associate with RNA segments
- RNA segments are different sizes. Each virus particle contained the same 8 fragments

The virus RNA alone cannot be translated must be transcribed first. 
Influenza virus segments are not naked RNA
- RNA in flu virus is highly structured 
- Held in this way through RNA-RNA interactions, RNA-protein interactions and protein- protein ineractions 
Protein is called N-protein. It wraps up the viral RNA 
Protein- protein interactions between the N-proteins
N protein can bind RNA and itself 

The influenza virus NP binds RNA and adjacent NP molecule to form NP multimers
NP binds to RNA backbone by positively charged residues that NP has
To bind to other NP a tail loop inserts into pocket on adjacent NP 

Cryo-EM was used to determine structure of RNA particles. At high resolutions. 

The RNP's (RNA and NPs) form double helical rods with RdRp at the end.
- RdRp- RNA dependent RNA polymerase

The rod is a RNA double helix
- The RNA strand are antiparallel
-The 5' and 3' ends are held together by RdRp and the other end of the rod forms a loop. 
- The NP-NP interaction allow formation of longchain of RNA
- Two antiparallel chains are linked by a 2nd NP-NP interface
- RNA is bound in an open groove and is accessible to the RdRp
-RNA is likely copied by the RdRp only with NP dissociation 

PB1, PB2, PA code for RdRp
HA= Hemagglutinin, surface spikes, attachment and fusion 
NP= Nucleocapsid protein, RNA binding 
NA= Neuraminidase activity, surface spikes 

M
M1= Matrix protein, major structural component, particle shape
M2= Ion channels (mRNA'S are spliced) 
- M2 is formed from a spliced variant of the M RNA 

NS
NS1= Non structural protein 1 : IFN antagonist, RNP export
NS2= Non structural protein 2: RNP export

Part of the flu life cycle must occur in the nucleus, as the mRNA is produced it is spliced. 

These 8 segments also code for additional protein products are made during infection
These are low abundance, but conserved across strains 
-The role of these accesory proteins are not well characterised
- Influenza A virus expresses 17 proteins