Spanish flu 1918

CDC

About 50 million people died as a result of the Spanish flu of 1918-19 and many of these were young and healthy (aged 15 to 34). This is surprising as flu usually kills the very young and the very old. It has been possible to obtain the RNA of the influenza type A virus that caused Spanish flu from a frozen body of a victim preserved in the Alaskan permafrost and from laboratory specimens of patient tissue preserved in formalin. This RNA has recently been sequenced (2005).  In addition, it has been possible to produce a recombinant virus that contains the HA and NA of the Spanish flu virus and also a complete virus with all eight genomic segments of the Spanish flu virus.

The reconstituted Spanish flu virus is exceptionally virulent in mice, producing very high titers of infectious virions. For example, it produced 39,000 times more virions in mouse lung cells after four days infection than a current human influenza strain. After two days of infection, mice lost 13% of their body weight (compared to only a transient loss with the human flu strain) and all died whereas none died from the human flu strain. In part, this high virulence is because the virus does not need an exogenous protease to cleave the surface hemagglutinin molecule.  The mice died of necrotizing bronchitis, bronchiolitis and alveolitis with adema and hemorrhage. However, there was no spread from the lungs to other organs. The Spanish flu originated wholly in birds and did not recombine with human flu viruses. Presumably the virus jumped from birds to humans because it acquired certain mutations that allowed it to infect and reproduce in human cells more easily. Certain of these mutations have been preserved in later generations of human flu. Notably, one mutation that seems to have occurred in Spanish flu also occurred when a different bird flu (H7N7) jumped to humans in 2003. 

The high virulence of the Spanish flu virus required the HA and polymerase genes. This was determined in studies in which the Spanish flu virus was compared with a chimeric virus with just the Spanish flu HA and NA. Indeed, when the HA gene of Spanish flu was replaced with one from a current human strain, the high virulence in mice was lost. Lower virulence also resulted when the three polymerases were replaced.