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. 2007 Oct;81(20):11139-47.
doi: 10.1128/JVI.01235-07. Epub 2007 Aug 8.

Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans

Jessica A Belser  1 , Xuihua Lu, Taronna R Maines, Catherine Smith, Yan Li, Ruben O Donis, Jacqueline M Katz, Terrence M Tumpey
Affiliations

Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans

Jessica A Belser et al. J Virol. 2007 Oct.

Abstract

Before 2003, only occasional case reports of human H7 influenza virus infections occurred as a result of direct animal-to-human transmission or laboratory accidents; most of these infections resulted in conjunctivitis. An increase in isolation of avian influenza A H7 viruses from poultry outbreaks and humans has raised concerns that additional zoonotic transmissions of influenza viruses from poultry to humans may occur. To better understand the pathogenesis of H7 viruses, we have investigated their ability to cause disease in mouse and ferret models. Mice were infected intranasally with H7 viruses of high and low pathogenicity isolated from The Netherlands in 2003 (Netherlands/03), the northeastern United States in 2002-2003, and Canada in 2004 and were monitored for morbidity, mortality, viral replication, and proinflammatory cytokine production in respiratory organs. All H7 viruses replicated efficiently in the respiratory tracts of mice, but only Netherlands/03 isolates replicated in systemic organs, including the brain. Only A/NL/219/03 (NL/219), an H7N7 virus isolated from a single fatal human case, was highly lethal for mice and caused severe disease in ferrets. Supporting the apparent ocular tropism observed in humans following infection with viruses of the H7 subtype, both Eurasian and North American lineage H7 viruses were detected in the mouse eye following ocular inoculation, whereas an H7N2 virus isolated from the human respiratory tract was not. Therefore, in general, the relative virulence and cell tropism of the H7 viruses in these animal models correlated with the observed virulence in humans.

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Figures

FIG. 1.
FIG. 1.
Phylogenetic tree of selected H7 HA1 genes. This tree includes viruses examined in this study (in bold) as well as viruses within the H7 subtype associated with disease in humans prior to 2002 and avian viruses that share high homology with these viruses. Virus lineages are indicated with curved brackets.
FIG. 2.
FIG. 2.
Comparison of mean titers of influenza A H7 viruses recovered from mouse tissues. BALB/c mice were inoculated i.n. with 106 EID50/50 μl of each virus indicated. Tissues were collected on days 3 (A, C, and E) and 6 (B, D, and F) p.i. from three mice per group. Tissue homogenates were prepared and titrated in eggs. Virus end-point titers are expressed as mean log10 EID50/ml plus standard deviations. The limit of virus detection was 100.8 EID50/ml. ND, not determined.
FIG. 3.
FIG. 3.
Determination of proinflammatory cytokine TNF-α, IFN-α, and IFN-β levels in H7-infected mouse lungs. BALB/c mice (three mice/group) were inoculated i.n. with 106 EID50/50 μl of either H7N7 (A) or H7N2 (B) virus as shown, and lungs were removed at the indicated days p.i. and frozen at −70°C until processed. Clarified cell lysates from lungs homogenized in 1 ml PBS were assayed by enzyme-linked immunosorbent assay. The constitutive cytokine levels (horizontal lines) present in the lung were determined by harvesting normal, uninfected lungs of BALB/c mice. The mean cytokine levels plus standard deviations are shown (*, P < 0.0006; **, P < 0.02).
FIG. 4.
FIG. 4.
Comparison of mean titers of influenza A H7 viruses recovered from ferret tissues. Ferrets were inoculated i.n. with 107 EID50/ml of each virus indicated (three ferrets/group). Tissues were collected on day 3 p.i., with tissue homogenates prepared and titrated in eggs. Virus end-point titers are expressed as mean log10 EID50/g plus standard deviations for all tissues except the nasal turbinates (NT) and blood, whose titers are expressed as log10 EID50/ml. The limit of virus detection was 101.5 EID50/ml of tissue homogenate. OB, olfactory bulb.
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