4.2  Ferrets
Two H5N1 viruses isolated in Hong Kong during the 1997 outbreak were found to readily infect ferrets (Zitzow et al., 2002). Since then, more H5N1 isolates that are highly pathogenic for birds have been found to replicate in ferret lungs without prior host adaptation. The infections generally have been characterized by severe lethargy, fever, weight loss, transient lymphopenia, and virus replication in the upper and lower respiratory tract and in multiple organs including the brain. More importantly, the illness induced by these agents was more severe than that induced by recently isolated human H3N2 viruses. The lungs of H5N1-infected ferrets showed diffuse inflammation of interalveolar septa with infiltrates of mononuclear cells and intra-alveolar edema, regardless of the time post infection; in contrast to the scattered infiltrates seen with other influenza A viruses, these changes were observed throughout the lungs (Maines et al., 2005). Viral antigens were detected in alveolar bronchial cells or bronchioles in the majority of animals by day 3 post virus exposure. Brain tissues showed mononuclear cell infiltrates in the meninges, choroid plexus, and brain parenchyma, and viral antigens were detected in neurons in the same areas.
In an effort to determine why the H5N1 virus is more virulent for ferrets than seasonal influenza A isolates, Cameron et al. (2008) analyzed the expression of host innate immune response genes during the course of lethal infection. The authors found that many interferon response genes, including IFI44, ISG15 (G1P2), MX2, OAS1, OAS2, STAT1, TAP1, and UBE1L, were significantly upregulated ferrets infected with the H5N1 virus, in comparison to an H3N2 isolate. CXCL10, a chemoattractant of activated Th1 lymphocytes and natural killer cells, was also upregulated to a much greater extent in an H5N1 infection than with the H3N2 virus. CXCL10 and its receptor CXCR3 are thought to play a role in the temporal development of innate and adaptive immunity in concert with type I and II interferons (Neville et al., 1997). In support of that hypothesis, Cameron et al. (2008) found that treatment of H5N1-infected ferrets with AMG487, a CXCR3 antagonist, markedly reduced the severity of symptoms and delayed death, compared to untreated animals.
Vaccines (reviewed by Subbarao and Luke, 2007, Chen et al., 2008, Lalor et al., 2008, Mahmood et al., 2008) and a number antiviral compounds (Malakhov et al., 2006, Govorkova et al., 2007, Boltz et al., 2008b, Yun et al., 2008) have been tested in ferrets infected with H5N1 viruses very often have verified findings in mice (Malakhov et al., 2006, Govorkova et al., 2007, Boltz et al., 2008b, Yun et al., 2008).