| Highly pathogenic avian influenza viruses (HPAIV) H5N1 are endemic in poultry and can cause a systemic infection in a wide spectrum of avian and mammalian species, including humans. They have been transmitted from poultry back into wild waterbird populations over a large geographical area. Wild waterbirds are typically assumed to play no epidemiological role for HPAIV, and their role in HPAIV H5N1 spread and maintenance has been greatly debated. In this thesis, wild waterbirds were shown to have contributed to HPAIV H5N1 geographical spread in Europe during winter, by aggregating on unfrozen bodies of fresh-water along the 0°C isotherm (chapter 3). Experimental infection of a wader species indicated that the migratory condition, including high concentration of plasma corticosterone, could result in increased viral shedding, which was associated with severe disease (chapter 4). This may slow but not abrogate HPAIV H5N1 spread by migratory birds. Infected birds are the source of HPAIV H5N1 infection in mammals. Carnivores and scavengers are at high risk of infection due to their feeding habits. Red foxes fed infected bird carcasses were shown to develop milder disease than when infected by intra-tracheal inoculation (chapter 6). They remained asymptomatic and survived infection. Foxes and potentially other carnivores and scavengers naturally infected with HPAIV H5N1 thus may go undetected where outbreaks in birds occur, potentially dispersing the virus locally. Experimental inoculation of cats directly into the digestive tract resulted in systemic infection, proving the intestine as a portal of entry for these viruses (chapter 7). This is unusual as influenza viruses typically enter and replicate in mammals' respiratory tract. Unexpectedly, HPAIV H5N1 inoculated via the intestine exhibited marked endotheliotropism, while those inoculated via the trachea infected mostly epithelial and parenchymal cells, illustrating HPAIV H5N1 tropism plasticity. The tissue tropism of influenza viruses is a major determinant of their virulence and transmissibility in mammals. A mathematical model integrating parameters of pathogenesis demonstrated that respiratory tissue tropism has a major impact on influenza virus reproductive fitness, providing insights on potential mechanisms driving the evolution of zoonotic, pandemic and seasonal influenza viruses in humans (chapter 8). |
