Letter | Published:

Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus

Abstract

The influenza pandemic of 1918–19 was responsible for about 50 million deaths worldwide1. Modern histopathological analysis of autopsy samples from human influenza cases from 1918 revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary oedema, haemorrhage and rapid destruction of the respiratory epithelium2. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show, in a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5. This was in contrast with smaller host immune responses as measured at the genomic level, accompanied by less severe disease pathology and delays in death in mice infected with influenza viruses containing only subsets of 1918 genes. The results indicate a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza virus requires the use of the fully reconstructed virus. With recent concerns about the introduction of highly pathogenic avian influenza viruses into humans and their potential to cause a worldwide pandemic with disastrous health and economic consequences, a comprehensive understanding of the global host response to the 1918 virus is crucial. Moreover, understanding the contribution of host immune responses to virulent influenza virus infections is an important starting point for the identification of prognostic indicators and the development of novel antiviral therapies.

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Acknowledgements

We thank K. A. Walters, M. J. Korth, J. Fornek and B. Paeper for discussions and assistance in manuscript preparation. This work was partly supported by grants from the National Institutes of Health (to A.G.S., P.P., J.K.T. and M.G.K.) and by the Ellison Medical Foundation (P.P. and C.F.B).

Author information

Correspondence to John C. Kash.

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Competing interests

Raw data on expression microarrays are available at http://expression.microslu.washington.edu. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Figure 1: Photomicrographs of lung sections from mice infected with influenza A virus, stained with haematoxylin and eosin.
Figure 2: Increased and earlier expression of genes associated with the activation of key immune cells in mouse lung infected with r1918 influenza virus.
Figure 3: Increased activation of inflammatory and death receptor gene expression by r1918 influenza virus.
Figure 4: Functional relationships of activated of cell death responses during infection with r1918 influenza virus.

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