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. 2012 Sep;86(17):9211-20.
doi: 10.1128/JVI.00887-12. Epub 2012 Jun 20.

Analysis by single-gene reassortment demonstrates that the 1918 influenza virus is functionally compatible with a low-pathogenicity avian influenza virus in mice

Li Qi  1 , A Sally Davis, Brett W Jagger, Louis M Schwartzman, Eleca J Dunham, John C Kash, Jeffery K Taubenberger
Affiliations

Analysis by single-gene reassortment demonstrates that the 1918 influenza virus is functionally compatible with a low-pathogenicity avian influenza virus in mice

Li Qi et al. J Virol. 2012 Sep.

Abstract

The 1918-1919 "Spanish" influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight "7:1" chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus.

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Figures

Fig 1
Fig 1
Weight loss of mice infected with parental 1918 influenza and AI viruses and eight chimeric 7:1 1918 influenza viruses bearing each of the gene segments of the AI H1N1 virus, respectively. Seven- to eight-week-old female BALB/c mice were intranasally inoculated with 103 PFU of the indicated viruses (see Table 2 and color-coded key) and weighed daily (5 mice per virus per group). P.I., postinoculation.
Fig 2
Fig 2
Histopathology and influenza virus antigen distribution for selected viruses. Matched sections of day 5 postinfection lungs (original magnification, ×100). H&E stains are shown in the left column, and influenza virus A antigen immunohistochemistry is shown in the right column with the DAB end product counterstained with hematoxylin. (A and B) Infection with the AI virus, demonstrating the absence of histopathologic changes and influenza virus antigen except rare, multifocal labeling of the bronchial epithelium (arrow). (C and D) Infection with the 1918 virus, showing severe multifocal changes, including transmural necrotizing bronchitis (arrow) and multifocal moderate-to-severe alveolitis with multifocal pulmonary edema (box) and influenza virus antigen in bronchial epithelium (arrow) and alveolar epithelial cells. (E and F) Infection with the 1918AI-PB2 virus, showing a similar absence of histopathologic changes comparable to the AI virus, accompanied by slightly stronger labeling of bronchial epithelium. (G and H) Infection with 1918AI-PB2-K627, showing similar histopathology, including transmural necrotizing bronchitis (arrow) and multifocal moderate-to-severe alveolitis with multifocal pulmonary edema (box) and influenza virus antigen distribution in bronchial epithelium and alveolar epithelial cells similar in distribution to the parental 1918 virus.
Fig 3
Fig 3
Weight loss of mice infected with PB2-K627E-modified 1918 (1918PB2-E627) and the PB2-E627K-modified 7:1 1918:AI chimeric (1918AI-PB2-K627) influenza viruses. Seven- to-eight-week female BALB/c mice were intranasally inoculated with 103 PFU of the indicated viruses (see Table 2 and color-coded key) and weighed daily (5 mice per virus per group).
Fig 4
Fig 4
Histopathology and neutrophil distribution for 1918 and 1918AI-HA viruses. Matched sections of day 5 postinfection lungs (original magnification, ×100). H&E stains are shown in the left column, and myeloperoxidase immunohistochemistry is shown in the right column with the DAB end product counterstained with hematoxylin. (A and B) 1918 virus-infected mice, showing severe multifocal changes and numerous myeloperoxidase-positive cells (neutrophils) prominently in the smallest airways, bronchioles, and alveoli. (C and D) 1918AI-HA virus-infected mice, showing similar histopathologic changes to 1918 and a comparable number of neutrophils in correlation with the histopathology.
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