Wednesday, 29 April 2009

Swine flu

Some notes on Swine Flu prepared mid-day 28/4/09


The Mexican outbreak of 18 March is of a H1N1 strain of influenza A virus. As was the Spanish flu of 1918, where lethality was high (50 x 10^6 dead: 500 x 10^6 infected worldwide).


Geneome -- is 8 pieces of negative strand RNA. They can re-associate in mixed infections with other strains or sub-strains.


Proteome -- The genome codes for 11 proteins. Prominent coat proteins (therefore targets for antibodies) are Haemagglutinin (HA), Neuraminidase (NA), and M2 ion-channel. (A haemagglutinin coagulates blood by binding to red blood cells.) HA is cut into two by a host protease (forming HA1 and HA2) contributing to the great variability. The identity of the amino acid at the cut site can affect virulence.


Infection -- Droplet infection of the nose, throat and lungs (or contagion followed by subsequent touching of nose or mouth). The virus binds to sialic acid residues of glycoproteins on epithelial cells by way of the HA protein. The ingested virus in the acidic endosome would be subjected to digestion so it has to escape. It is thought that the M2 ion-channel has a role in releasing the RNA from the coat, and possibly the endosome. It may simply allow the virus interior to become acidic like the endosomal lumen. The RNA replicates first to a positive strand and from that to more negative strands. The daughter virion assembles its coat proteins near the inside surface of the host cell and buds out through the cell membrane. Only some 10% of progeny contain the correct 8 pieces of RNA. The NA protein's sole function is to cut the progeny virus away from the now dying host cell.


Lethality -- arises because the virus activates a cytokine storm, a feed-back loop between cytokines and immune cells. There are many cytokines including tumor necrosis factor alpha, and interleukins; and of the interleukins some are inflammatory (e.g. 1 and 6) while others are anti-inflammatory (10 etc.). A storm in the lungs causes inflow of macrophages which destroy lung tissue and cause inflow of liquid; and respiratory distress. It is a striking feature of death by cytokine storm that it is those with the BEST immune response who die; healthy young 15 - 40 year-olds. (I wonder if aspirin might save lives! I shall certainly take aspirin with me if I go to Mexico [See J. Biol. Chem. 272, pp. 25693-9])


Chemotherapy -- The two main targets are M2 protein (blocked by amantadine, and its relatives, which cause drug resistance if overused), and Oseltamivir (= tamiflu, etc.) and other similar drugs which are neuraminidase inhibitors. These are not effective against the cytokine storm. 


Vaccines -- Though there are vaccines already prepared against H1N1 strain of influenza A, they are not effective against this sub-strain. Illustrating the VARIABILITY of the HA and NA antigens. With new methods, effective monoclonals can be made in some 6 weeks against the specific sub-strain involved, for use in passive antibody therapy.


Why lethal in Mexico but not elsewhere? -- I suppose that there is recombination at work; my speculation is that Europeans already have immunity to one of the parents of this new sub-strain.




Ian West

12 Longhirst Village,


Tel: (0)1670 791880




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