Spanish Influenza, Part 1 (Biochemistry)

I        In March 2004, Science Magazine published a trio of papers concerning the influenza virus from the 1918 pandemic known as the Spanish Influenza.  Typical at-risk populations for influenza are the very young and quite old, making a histogram of fatalities versus age appear U-shaped (Figure 2.1).  The influenza of 1918 was peculiar because its graph was W shaped (Figure 2.1).  There was a spike in the middle representing a large amount of deaths for those aged 15 – 45.  Not only that, but this wave of influenza infected nearly one third of all Americans and killed roughly 30 million people worldwide.  These numbers are in stark contrast to the Center for Disease Control reported 5 – 20% infection rate of the US population during a “typical” flu year.  Researchers would like to understand why this virus was so virulent and hope to apply their findings to future pandemic outbreaks.

                Influenza A infects all kinds of animals - from humans to whales!  Scientists tend to focus on bird (avian), pig (swine), and human influenzas because relationships between the three are very interesting.  

The reservoir of influenza A viruses lies within the gastrointestinal tracts of birds.  These viruses can cause birds to suffer mild symptoms, but may also be asymptomatic or lethal.  A pig can become infected by an avian virus and develop a runny nose or fever.  (Can you imagine a pig with a runny nose?  Poor thing!)  A human, however, most likely is not able to be infected by an avian virus.  Why?

                In order to become “infected” by a virus, our cells must allow a virus inside them.  Think of your body as a neighborhood, your cells as homes within the neighborhood and viruses as burglars.  Obviously the burglars (viruses) want to break inside the homes (cells) and steal valuables (replication machinery), but neighborhoods have police and neighborhood watches (immune system) to ensure this does not happen.  Houses (cells) also have locks, which need keys!

Now, if a burglar breaks violently into a house, it is more likely that someone will notice something amiss and check it out.  It is to the benefit of the burglar to have a key, gain entrance quietly, and do damage once safely inside.  A virus works by carrying a key to our cells’ locks, softly entering without harm, then stealing our cells’ machinery and nutrients to replicate itself over and over until our cells can hold no more virus particles, at which point, the cell bursts open and spills all the newly made viruses into the neighborhood to infect more nearby cells.  Viruses are gross. 

A certain protein, known has hemagglutinin (key), on the influenza viral surface can recognize a specific molecule (lock) found on the outside of host cell.  As long as hemagglutinin can properly bind the molecule (a sialic acid bound to a galactose, which is bound to some cellular protein), then the virus can enter the cell.  The sialic acid can be linked to the galactose one of two ways: α2,3 or α2,6.  The gastrointestinal tract of birds is coated with cells bearing α2,3-linked sialic acid.  The respiratory tract of pigs has both.  The human respiratory tract only has α2,6-bound molecules.  The hemagglutinin of an infectious avian virus is not a proper key for human cells and thus cannot infect them.  Most researchers agree that for an influenza virus to jump from birds to humans, the hemagglutinin molecule must gain the ability to bind α2,6 linked sialic acid.

Fifteen different hemagglutinin proteins have been identified.  Each time one of these proteins has gained the ability to infect human cells, it has resulted in a pandemic.  A 1957 pandemic was due to H2, the 1968 pandemic was due to H3 and the 1918 pandemic was due to H1.

However, the gain of hemagglutinin binding α2,6 linked sialic acid can only be part of the answer to the question of virulence.  The 1957 and 1968 pandemics were far less severe than 1918.  

Several theories do exist as to why the Spanish flu was so deadly.  Due to World War I, many young men were living in close quarters at army camps, so the disease was able to spread quickly.  A lack of medicine due to the war also meant that secondary infections (such as pneumonia) were more likely to lead to death.   However, researchers believe that the virus itself could answer a multitude of questions if we could simply study it.  Unfortunately, no intact virus has survived.  Much like Jurassic Park, we’ve had to find the “Dino DNA” (or viral DNA, as it were).  Believe it not, scientists were able to find it! 

Stay tuned…

References

Histogram: The x axis represents age and the y axis represents how many people died of influenza at that age.

Seasonal influenza information: http://www.cdc.gov/flu/about/qa/disease.htm

Stevens, J. et al. “Stucture of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus.” Science (2004) 303, pgs 1866 – 1869.

Gamblin, S. J. et al. “The Structure and Receptor Binding Properties of the 1918 Influenza Hemagglutinin.” Science (2004) 303, pgs 1838 – 1842

Holmes, Edward C. “1918 and All That.” Science (2004) 303, pgs 1787 – 1788.