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. 2011 Apr 10;412(2):426-34.
doi: 10.1016/j.virol.2011.01.029. Epub 2011 Feb 18.

The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding

Li Qi  1 , John C Kash, Vivien G Dugan, Brett W Jagger, Yuk-Fai Lau, Zhong-Mei Sheng, Erika C Crouch, Kevan L Hartshorn, Jeffery K Taubenberger
Affiliations

The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding

Li Qi et al. Virology. .

Abstract

Pandemic influenza viral infections have been associated with viral pneumonia. Chimeric influenza viruses with the hemagglutinin segment of the 1918, 1957, 1968, or 2009 pandemic influenza viruses in the context of a seasonal H1N1 influenza genome were constructed to analyze the role of hemagglutinin (HA) in pathogenesis and cell tropism in a mouse model. We also explored whether there was an association between the ability of lung surfactant protein D (SP-D) to bind to the HA and the ability of the corresponding chimeric virus to infect bronchiolar and alveolar epithelial cells of the lower respiratory tract. Viruses expressing the hemagglutinin of pandemic viruses were associated with significant pathology in the lower respiratory tract, including acute inflammation, and showed low binding activity for SP-D. In contrast, the virus expressing the HA of a seasonal influenza strain induced only mild disease with little lung pathology in infected mice and exhibited strong in vitro binding to SP-D.

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Figures

Figure 1
Figure 1. Weight loss and survival of mice infected with wild-type influenza viruses and chimeric influenza viruses expressing the HA genes of different influenza viruses
(A) Representative weight loss of mice infected with rescued influenza viruses. Eight-to-ten-week-old female BALB/c mice were intranasally inoculated with 2 × 105 PFU of the indicated viruses and weighed daily (n=5 mice per virus per group). *Note that by day 4 post infection, one animal each infected with 1957-HA, 1968-HA, and 2009-HA had died. ***Note that by day 6 post infection, 3 animals infected with 1918-HA had died. (B) Kaplan-Meier survival curve of 8-to-10-week-old female BALB/c mice intranasally inoculated with 2 × 105 PFU of the indicated viruses (n=20 mice per virus group, except 1918-HA virus which had n=25).
Figure 1
Figure 1. Weight loss and survival of mice infected with wild-type influenza viruses and chimeric influenza viruses expressing the HA genes of different influenza viruses
(A) Representative weight loss of mice infected with rescued influenza viruses. Eight-to-ten-week-old female BALB/c mice were intranasally inoculated with 2 × 105 PFU of the indicated viruses and weighed daily (n=5 mice per virus per group). *Note that by day 4 post infection, one animal each infected with 1957-HA, 1968-HA, and 2009-HA had died. ***Note that by day 6 post infection, 3 animals infected with 1918-HA had died. (B) Kaplan-Meier survival curve of 8-to-10-week-old female BALB/c mice intranasally inoculated with 2 × 105 PFU of the indicated viruses (n=20 mice per virus group, except 1918-HA virus which had n=25).
Figure 2
Figure 2. Lung pathology induced with different influenza A viruses
Pathology and immunohistochemistry of influenza A virus-infected mouse lung tissue. Photomicrographs of hematoxylin-and-eosin-stained tissue sections (A, C, E, G, I, K) and immunohistochemically-stained sections (B, D, F, H, J, L) to detect influenza viral antigen from mice infected with isogenic viruses expressing different HAs at 4 dpi. Viral antigen is stained red-brown on a hematoxylin-stained background. The 1918- HA virus (A, B) induced a moderate-severe alveolitis and bronchiolitis with viral antigen in both bronchiolar epithelial and alveolar lining cells. The 1957- HA virus (C, D), the 1968 - HA virus (E, F), and the 2009- HA virus (G, H) induced similar pathologic changes with mild-moderate alveolitis and bronchiolitis with viral antigen in both bronchiolar and alveolar lining cells. The NY312 virus (I, J, K, H) induced no pathologic changes but did show viral antigen staining in tracheobronchial and bronchiolar epithelial cells and occasional alveolar macrophages [Original magnifications 100×].
Figure 3
Figure 3. Pathology and immunohistochemistry of influenza A virus-infected mouse lung tissue
Photomicrographs of hematoxylin-and-eosin-stained tissue sections and immunohistochemically-stained sections to detect influenza viral antigen from mice infected with isogenic viruses expressing different HAs at 4 dpi. Viral antigen is stained red-brown on a hematoxylin-stained background. (A-C) 1918-HA virus induced an alveolitis with a mixed cellular inflammatory infiltrate including numerous neutrophils (arrowheads), lymphocytes, and macrophages (arrows). Viral antigen was detected in alveolar macrophages (B, arrows), and alveolar lining cells (C, arrows). Viruses expressing the 1957 (D-F), 1968 (G-I), or 2009 (J-L) pandemic HAs induced similar pulmonary pathologic changes, consisting of an alveolitis with a mixed cellular inflammatory infiltrate including numerous macrophages (arrows). Viral antigen was detected in alveolar macrophages (E, H, K, arrows), and alveolar lining cells (F, I, L, arrows). The NY312 (P-R) virus induced little appreciable pulmonary pathologic changes, with no alveolitis (M, P). The lungs of NY312 virus-infected mice showed occasional viral antigen positive alveolar macrophages (N, arrows), but no alveolar lining cell staining (O) [Original magnifications 1000×].
Figure 4
Figure 4. Expression of CCL2 (MCP-1) and CSF3 (G-CSF) in lungs of mice infected with chimeric influenza viruses expressing the HA genes of different influenza viruses
Cytokine and chemokine protein concentrations were determined from mouse lung homogenates as described in the methods from infected animals at indicated days post infection (note that no samples were available for 2009-HA at day 5 post infection) A) CCL2 (MCP-1) B) CSF3 (G-CSF). Mean protein concentrations are shown in pg/g ±SD. See key for different viruses.
Figure 5
Figure 5. Lung titers in mice infected with wild-type influenza viruses and chimeric influenza viruses expressing the HA genes of different influenza viruses
Virus titers in the lungs of infected BALB/c mice (n=3) at days 1, 3, 4, and 6 post infection, plotted as PFU per gram (Log10) of lung tissue as determined by plaque assay. N.D. = Not done. B.D. = below the limit of detection of the assay.
Figure 6
Figure 6. SP-D neutralization assay with wild-type influenza viruses and chimeric influenza viruses expressing the HA genes of different influenza viruses
Chimeric IAV expressing the HA of pandemic or seasonal IAV (see Table 1) were tested for their ability to bind to SP-D using a SP-D neutralization and plaque reduction assay as described in the Material and Methods section. Data are presented as mean ± SD. Two-tailed P values were calculated with an unpaired t test. (P = 0.002)
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