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. 2013 Jun 11;44(1):41.
doi: 10.1186/1297-9716-44-41.

The 2009 pandemic (H1N1) viruses isolated from pigs show enhanced pathogenicity in mice

Yongtao Li  1 , Wei Zou, Guangmin Jia, Jianjiang Ke, Jiping Zhu, Xian Lin, Hongbo Zhou, Meilin Jin
Affiliations

The 2009 pandemic (H1N1) viruses isolated from pigs show enhanced pathogenicity in mice

Yongtao Li et al. Vet Res. .

Abstract

Since the emergence of the 2009 pandemic (H1N1) virus (2009/H1N1) in April 2009, cases of transmission from humans to pigs have been reported frequently. In our previous studies, four 2009/H1N1 variants were isolated from pigs. To better understand the phenotypic differences of the pig isolates compared with the human isolate, in this study mice were inoculated intranasally with different 2009/H1N1 viruses, and monitored for morbidity, mortality, and viral replication, cytokine production and pathological changes in the lungs. The results show that all isolates show effective replication in lungs, but varying in their ability to cause morbidity. In particular, the strains of A/swine/Nanchang/3/2010 (H1N1) and A/swine/Nanchang/F9/2010 (H1N1) show the greatest virulence with a persisting replication in lungs and high lethality for mice, compared with the human isolate A/Liaoning /14/2009 (H1N1), which shows low virulence in mice. Furthermore, the lethal strains could induce more severe lung pathological changes and higher production of cytokines than that of other strains at an early stage. Amino acid sequence analysis illustrates prominent differences in viral surface glycoproteins and polymerase subunits between pig isolates and human strains that might correlate with their phenotypic differences. These studies demonstrate that the 2009/H1N1 pig isolates exhibit heterogeneous infectivity and pathogencity in mice, and some strains possess an enhanced pathogenicity compared with the human isolate.

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Figures

Figure 1
Figure 1
Weight loss and mortality of mice inoculated with different 2009/H1N1 virues in mice. Six-week-old BALB/c mice were inoculated intranasally with 103TCID50 viruses, with 10 mice per group. The mice that lost 25% of its preinoculation body weight were humanely euthanized with quick cervical dislocation and the data were expressed as the survival percentage of mice infected with 103TCID50 viruses (A). Body weight of mice infected with of each virus was measured for 14 dpi (B).
Figure 2
Figure 2
Comparison of the viral replication in mice of different 2009/H1N1 strains in a dose dependent manner. Five mice of each group were infected with a dose series of the viruses (102-105 TCID50), euthanized at 3 and 6 dpi and the titers in lung homogenates of mice were determined using absolute quantitative PCR on 3 (A) and 6 dpi (B) respectively. The values were calculated through a standard curve which was generated by ten-fold serial dilutions of standard plasmid harboring NP gene of 2009/H1N1 virus. The results are presented as mean ± SEM of virus copy numbers. × indicates the infection dose in the groups exceeds the content of the original virus. ND means the virus could be not detected. Significant differences were observed at 3/10 and F9/10 compared with 5/10, 6/10 and LN/09 (* p < 0.05).
Figure 3
Figure 3
Comparison of Lung pathology in mice infected with different H1N1/2009 viruses on 5 dpi. In 3/10-infected mice lungs, signs of acute interstitial pneumonia with infiltration of large amount of lymphocytes (arrow a) and atelectasis (arrow b) were present. Lung tissues in lesion areas of F9/10-infected mice show acute pneumonia with alveolar wall thickening, large amounts of infiltration of inflammatory cells and bleeding (arrow c). The pathological changes of lung tissues infected with 5/10 and 6/10 viruses just show certain alveolar wall thickening (arrow d) and bronchial exudates (arrow e). LN/09-infected mice only show slight alveolar wall thickening in lung lesions (arrow f). Images were obtained on an Olympus BX-50 light microscope at 50-fold original magnifications (50×).
Figure 4
Figure 4
Cytokine production of lungs in BALB/c mice infected with different H1N1/2009 viruses. On 3, 5, 7 and 9 dpi respectively, the lung homogenates from mice inoculated with the four 2009/H1N1 pig isolates (3/10, F9/10, 5/10 and 6/10), a human isolate designed LN/09 and control mice were prepared and tested for the production of cytokines IL-1β, IL-6, IL-10, IL-12 (p40), TNFα and IFN-γ by ELISA assay. The results are presented as mean ± SD (n = 3) of protein levels.The statistical analysis at each time point was performed compared to data for LN/09 virus or other viruses with lower cytokine levels (* p < 0.05).
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