1. Influenza Virus: Evolution in real time

2. Influenza (FLU) 20,000 human deaths annually in USA
1918 Spanish flu killed 50 –100 million people globally (about 20% of world population)
Direct economic cost of flu about 4.6 billion USD per year

3. PANDEMICS Since 1880’s, there have been six flu pandemics
1889, 1918, 1968, 1977, 2009
What causes pandemics?

4. Influenza Taxonomy
Three principle clades of influenza: A, B, C ( analogous to genera)
A found widely in animals (highest diversity in birds), but mammals (including humans as well)
B found in humans and seals
C found in humans and pigs (least pathogenic, most diverged)

5. INFLUENZA STRUCTURE single stranded RNA protein sheath (caspid)
8 gene segments (A&B)
three proteins extrude: hemagglutinin (HA), neuraminidase (NA), and matrix 2. HA and NA bind to cell membrane. hemagglutinin

6. INFLUENZA glycoproteins
HA and NA are the principle target of the immune response
Influenza A has 16 types of HA proteins and 9 NA types (most types in birds)

7. INFLUENZA IMMUNE RESPONSE
Influenza A has 16 types of HA proteins and 9 NA types (most types in birds)
The HA protein binds to sialic acid receptors on the cell surface. Birds have one type of receptor (SAα2,3 intestinal), humans have SAα2,6 (respiratory system), pigs have both (in all organs).
HA types don’t necessarily determine receptor affinity

8. INFLUENZA IMMUNE RESPONSE
Host antibodies recognize specific HA and NA structures, that structure is determined by the amino acid sequence in the protein
Novel HA and NA structures go unrecognized, allowing influenza virus to replicate

9. INFLUENZA: Two types of evolution
mutational: change in the RNA sequence of a gene segment. mutation rate: 1 x 10-3 to 8 x 10-3 substitutions per site per year (vertebrate autosomal DNA: 1 x 10-(9-12))

10. antigenic drift: mutations that change the protein amino acid composition (i.e. non-synonymous substitutions) especially at the antigenic sites.
In surviving lineage they identified 33 amino acid replacements in antigenic sites and 10 in non antigenic sites. In extinct lineages found 31 replacements in antigenic sites and 35 in non-antigenic sites.
What does this mean?

11. REASSORTMENT
When a host cell is simultaneously infected by two different strains, gene segments can be re-assorted among subsequence viral copies
(Note: this is a great example of non- Darwinian evolution)

12. HOST Switching NP protein usually causes virus to be host specific.
But the virus can jump species
Usually more virulent

13. h5n1 influenza endemic in Southeast Asia
reservoir in wild and domestic waterfowl
in mid-2000s spread via migratory birds to Europe and Middle East (only established in Egypt)
highly fatal (60% of human patients die, infected birds typically die too)
human receptor in lower respiratory tract probably explains why human to human transmission non-existant

14. REASSORTMENT AND HOST SWITCHING
Working model is that reassortment facilitates host switching

15. Influenza pathogenicity is a by-product of host switching

16. REASSORTMENTS cause influenza pandemics
Bring completely novel gene segment combinations together

17. 2009 Swine flu
First detected in Mexico, then quickly in the US in March 2009
During the subsequent 3-4 weeks, it spread to at least 30 countries
WHO Pandemic level 5 of 6

18. REASSORTMENT in 2009 Swine Flu h1n1

19. 2009 Pandemic H1N1 spread very fast across the world
Originated either in Mexico or USA

20. Reassortment is on-going

21. Influenza persistence depends on ecology and spillover