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User name	Nicolas Tchitchek
Email	nicolas.tchitchek@ihes.fr
Phone / Fax number	0033610887604 /
Location	Institut des Hautes Ã‰tudes Scientifiques (Systems Epigenomics Group) - 35, route de Chartres - 91440 Bures-sur-Yvette, FRANCE

Scientific description

From abstract:
The 1918 pandemic influenza virus was the most devastating infectious agent in human history, causing fatal pneumonia and an estimated 20-50 million deaths worldwide. Previous studies indicate a prominent role of the HA gene in efficient replication and high virulence of the 1918 virus in mice. It is, however, still unclear whether the high replication ability or the 1918 HA gene is required for 1918 virus to exhibit high virulence in mice. Here, we examined the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus (A/Kawasaki/173/2001; K173) in a mouse model. In addition to the 1918 HA, we demonstrated the role of viral RNA replication complex in efficient replication of viruses in mouse lungs, whereas only HA gene is responsible for lethality in mice. Global gene expression profiling of infected mouse lungs revealed 1918 HA was sufficient to induce transcriptional changes similar to the 1918 virus, despite difference in lymphocyte gene expression. Increased expression of genes associated with the acute phase response and protein ubiquitination pathway were enriched during 1918 and 1918HA/K173 infections, whereas reassortant viruses bearing the 1918 viral RNA polymerase complex induced transcriptional changes similar to K173 virus. Taken together, these data suggest HA and the viral RNA polymerase complex are critical determinants of Spanish influenza pathogenesis, but only HA, and not the viral RNA polymerase complex and NP, is responsible for extreme host responses observed in mice infected with the 1918 influenza virus.

Technical description

From material & method section:
Mice were intranasally inoculated with 106 PFU of virus (n = 45) or inoculated with phosphate-buffered saline (n = 6), and whole lungs were collected on days 1, 3, and 5 p.i. from infected animals (n = 3/time point/group) and from control animals (n = 2/time point) for microarray analysis. Two of 3 mice infected with either 1918 virus or 1918HA/K173 virus died by day 5 p.i. RNA was isolated from total lung homogenates and fluorescently labeled probes were generated from each sample using Agilent one-color LowInput Quick Amp Labeling Kit (Agilent Technologies). Individual cRNA samples were hybridized to oligonucleotide microarrays for gene expression profiling using Whole Mouse Genome Microarray Kit (G4122A; Agilent Technologies), as previously described. RNA isolated from control animal lungs served as an uninfected reference. Quantitative reverse transcription-PCR was performed on mouse lung samples using a primer-probe set targeting the viral M sequence. A single biological replicate infected with 1918PB1/K173 virus at day 3 p.i. was confirmed to be uninfected and the sample was discarded from the dataset prior to analysis.

Reference

Watanabe T, Tisoncik-Go J, Tchitchek N, Watanabe S, Benecke AG, Katze MG, Kawaoka Y.
1918 HA and the viral RNA polymerase complex enhance viral pathogenicity, but only HA induces aberrant host responses in mice. J Virol. (2013)

Pubmed : http://www.ncbi.nlm.nih.gov/pubmed/23449804