Highly pathogenic avian Influenza viruses (HPAIV) cause devastating outbreaks in poultry associated with huge economic losses due to the high level of mortality and the imposed trade limitations. These HPAIV also represent a significant risk to human health, as some HPAIV are able to cross the species barrier and cause a high level of mortality in humans as well. In addition, these viruses have the potential to evolve to more human-adapted viruses, which could lead to unusually deadly pandemics. Understanding which factors influence the emergence of HPAIV is therefore of prime importance for animal health and human health, in total agreement with the One Health concept. Acquisition of a multibasic cleavage site in the haemagglutinin is the first step in the emergence of a HPAIV. While this initial step is a stochastic virus-dependent event, we believe that the ability of the newly formed HPAIV to outcompete the parental low pathogenic avian influenza virus (LPAIV) is the actual key determinant controlling the emergence of HPAIV. The success rate of a newly formed HPAIV is currently unknown and is likely to depend on a multitude of factors including host (species, health status and history of prior LPAIV infections), parental LPAIV, animal husbandry and other environmental factors. Until now emergence of HPAIV has been observed only in Galliformes (such as chickens and turkeys), leading to the establishment of the dominant opinion according to which circulation of LPAIV in Galliformes is a prerequisite to the emergence of HPAIV. However, preliminary analyses of the 2015-2016 HPAIV outbreaks in France provide evidence that the currently circulating HPAIV may have emerged in ducks. By studying the predominant H5N9 HPAIV strain circulating in France, we will test the hypothesis that HPAIV can emerge in ducks. In addition, we will test the contribution of antibiotics-induced perturbations of the bacterial flora of the host to the emergence of HPAIV in chickens and ducks. Identification of host and anthropogenic factors influencing the emergence of HPAIV is critical because it may lead to adjustments of control measures to prevent further outbreaks.