Insights into the pathogenesis of the Spanish Flu

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One of the enduring mysteries of influenza is why the 1918 H1N1 influenza, better known as the Spanish Flu, was so unusually deadly. The 2009 H1N1 influenza was certainly capable of creating a pandemic but was not nearly as deadly. Granted most of the fatalities in 1918 had bacterial pneumonia that could probably have been cured today. However, the incidence of fatal viral pneumonia appears to have been much higher in 1918. This viral pneumonia was reported to cause “massive acute pulmonary hemorrhage or pulmonary edema”.

New techniques in reverse genetics have allowed two groups, one from the CDC and the other from Japan, to recreate the 1918 virus. This allows either the whole 1918 virus or specific genes or genetic segments to be directly tested on animals.

Contemporary H1N1 influenza viruses infect the upper airways only. The reconstructed 1918 H1N1 virus creates an intense infection in the lungs of non-human primates that culminated in acute respiratory failure and death. Necropsy results have shown extensive pulmonary edema and hemorrhages not found in animals infected with contemporary H1N1 viruses. Microarray analysis showed that the 1918 virus infected animals mounted a strong but atypical innate immune response.

So what is it about the 1918 H1N1 influenza virus that increases its virulence and triggers such a strong but atypical immune response?

Its been known for some time that the hemagglutinin (HA) gene –responsible for host cell selection and membrane fusion — is critical for the high virulence of the avian viruses. The 1918 H1N1 virus lacks the specific motif identified on the avian HA gene that has been attributed to its virulence. When the 1918 HA gene is added to an otherwise contemporary H1N1 virus, it produced a high lung titer causing severe lung damage in mice with infiltration by neutrophils and alveolar macrophages. The results were similar to the whole reconstructed 1918 H1N1 virus. The exact portion of the HA gene that is critical for its virulence is yet to be determined. It is not very surprising that a viral spike responsible for host cell binding and fusion is involved in expanding the target tissue to the lungs.

The role of the 1918 viral RNA polymerase complex in viral repication. (click to enlarge, from Watanabe & Kawaoka, 2011)

The viral RNA polymerase complex has also been implicated in the high  virulence of the 1918 virus. Unlike contemporary influenza viruses, the 1918 virus replicates in the nasal cavity but also along the trachea and within the lungs. As you can see in the figure to the left, the hybrid virus containing the 1918 RNA polymerase complex and NP gene  (PA, PB1, PB2, and NP genes) and the remainder from a contemporary H1N1 virus replicated in the same tissues as the complete 1918 virus. The contemporary H1N1 virus replicated only in the upper respiratory system. Here we have replication of the hybrid virus without the 1918 HA gene replicating in the lungs. Clearly more research is required to reconcile the HA and RNA polymerase complex results.

Other genes have been implicated in increasing the effectiveness of the 1918 virus but the results are more vague.  The availability to reconstruct all or part of the 1918 H1N1 virus along with the 2009 H1N1 pandemic virus and contemporary drifted H1N1 viruses should mean that we will be able to eventually unravel some of the mysteries of influenza but there is still a long road ahead.


Watanabe, T., & Kawaoka, Y. (2011). Pathogenesis of the 1918 Pandemic Influenza Virus PLoS Pathogens, 7 (1) DOI: 10.1371/journal.ppat.1001218

This review paper is freely available here.

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