Genetic insight into 1918 pandemic flu

9 January 2009

Influenza or flu is a highly infectious viral disease; seasonal epidemics occur due to minor genetic variation in the viral particles that allow them to evade the human immune system. Occasionally, a human flu virus may acquire a whole new segment of genetic material from another flu virus, such as a strain that normally infects birds or pigs. A virus that can infect humans, but which is genetically very different from previous strains, can cause a pandemic (world-wide epidemic), because humans have no resistance to the new strain. Pandemic flu not only causes a massive increase in infections, but may also have severe effects in unexpected groups; whilst epidemic flu is generally only serious in the very old, very young, or ill, previous pandemics have caused high mortality in otherwise fit young adults.

Based on previous experience, a new flu pandemic is in many ways overdue: there have been pandemics in 1918, 1957 and 1968, and the World Health Organization (WHO) is concerned that conditions favouring the emergence of a pandemic virus are…well known, and are increasingly being met” (see WHO report) and that there is a significant risk of another pandemic within the next few years. This is obviously a major public health concern, and substantial research efforts are going into developing candidate vaccines and treatments, and systems to deliver them should the need arise.

New genetic research has revealed the sequences of three key genes from the influenza H1N1 variant strain that caused the 1918 Spanish flu pandemic, which resulted in up to 50 million deaths. It was already known that the virulence of this strain was linked to its unusual capacity to invade the lungs and cause severe pneumonia; now a paper in the journal Proceedings of the National Academy of Sciences (PNAS) identifies three key genes that allowed the virus to do so.

The Japanese-American team generated 1918 pandemic viruses using DNA taken from lung tissue that came from victims of the pandemic. They then created viruses from a combination of the 1918 strain and a modern, low-virulence H1N1 virus, and assessed their virulence in ferrets, which are apparently a fairly good animal model of the human disease [Watanabe T et al. (2008) Proc Natl Acad Sci U S A. Dec 29, Epub ahead of print]. Most of the new recombinant strains showed only normal patterns of infection and spread, but one that produced the 1918 viral RNA polymerase complex and nucleoprotein showed virulence much more like that of the 1918 pandemic strain, including spread to the lower respiratory tract and
lungs.

A reassortant virus containing the 1918 viral RNA polymerase complex genes (PA, PB1, and PB2) and nucleoprotein (NP) gene showed virulence properties in the upper and lower respiratory tracts of ferrets that closely resembled those of wild-type 1918 virus. The authors conclude that their findings “strongly implicate the viral RNA polymerase complex as a major determinant of the pathogenicity of the 1918 pandemic virus”. The 1918 RNA polymerase complex may be involved in generally increased viral replication capacity, or in tissue-specific increased replication capacity; for example, modulating interactions with a cellular factor that is present in the lower respiratory tract

Comment: Although not in every respect as exciting as it sounds, given that genetic virulence factors and an unusual propensity to colonise the lungs were already known for the 1918 influenza virus, the findings of this research are nevertheless important since they link the key genetic virulence factors from the 1918 flu virus with lung spread and invasion. This sort of information will inform ongoing monitoring of emerging viral strains to identify potentially dangerous ones, as well as contributing to research into new forms of anti-viral drugs to combat the most serious effects of a pandemic strain. Intervention to avoid spread of the virus to the lungs during an infection could prevent many deaths.

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