Dimerized STAT proteins subsequently migrate to the nucleus and stimulate transcription [63]. H5N1 virus infection. Transient constitutively-active STAT-3 transfection in chicken cells significantly reduced pro-inflammatory response to H5N1 virus infection; on the other hand, chemical inhibition of STAT-3 activation in duck cells increased pro-inflammatory gene expression following H5N1 virus infection. Collectively, we propose that elevated pro-inflammatory response in chickens is a major pathogenicity factor of HPAI H5N1 virus infection, mediated in part by the inhibition of STAT-3. == Electronic supplementary material == The online version of this article (doi:10.1186/s13567-014-0118-3) contains supplementary material, which is available to authorized users. == Introduction == Avian influenza A viruses continue to spread globally causing PAP-1 (5-(4-Phenoxybutoxy)psoralen) millions of poultry deaths and are significant zoonotic pathogens [1]. In particular, Eurasian lineage highly pathogenic avian influenza (HPAI) H5N1 virus infection causes severe disease in humans with a fatality rate of about 60% [2]. Most human influenza pandemics of the 20thcentury had been caused by influenza A viruses (IAVs) that originated, either wholly or in part, from avian TNRC21 influenza A viruses [3]. Ducks and waterfowl are reservoirs for most IAVs, including the hemagglutinin (HA) and neuraminidase (NA) subtypes that have caused previous human pandemics [4]. Despite being susceptible to infection with a wide range of IAVs, such birds often show little or no clinical signs [5,6]. In contrast, most HPAI H5N1 virus strains produce very severe disease in chickens, turkeys and quails often causing up to 100% mortality within 23 days [7,8]. With their natural resistance, ducks support genetic reassortment of influenza viruses providing a mechanism of evolution of genetically diverse IAVs including HPAI H5N1 viruses [9-11]. The rapid onset of fatal disease in chickens and no evidence of clinical disease in ducks suggests that there are potential differences in the innate immune mechanisms between these two important avian hosts. Recent evidence shows that the resistance of ducks to HPAI virus infection is not absolute. Contemporary Eurasian lineage HPAI H5N1 viruses have caused large numbers of deaths PAP-1 (5-(4-Phenoxybutoxy)psoralen) in both poultry and water fowl including ducks. Experimental infection of Pekin ducks (Anas platyrhynchos) with a HPAI H5N1 clade 2.2.1 virus (A/turkey/Turkey/1/2005) causes fatal infection [12], suggesting that certain clades of contemporary Eurasian lineage HPAI H5N1 viruses are able to overcome the natural innate resistance of ducks. PAP-1 (5-(4-Phenoxybutoxy)psoralen) The unusual severity of HPAI H5N1 virus infection in humans, in contrast to seasonal H3N2 or H1N1 influenza viruses, has been regarded to be due to hyper-acute induction of pro-inflammatory cytokines often referred as hypercytokinemia or cytokine storm [13-15]. Pigs show mild or no clinical signs following HPAI H5N1 virus infection [16]. We recently showed that the innate resistance of pigs to HPAI H5N1 virus is mediated through reduced pro-inflammation and infectious virus release [17]. These findings indicate that dysregulation of host pro-inflammatory response to infection is a key contributing factor to the morbidity and mortality of virulent influenza virus infections. Similarly a recent study found that excessive delayed inflammatory cytokine responses may contribute to the severe pathogenicity of HPAI H7N1 in chickens [18]. However, the pathophysiology of H5N1 virus infection in chickens and ducks remains unclear. To further our molecular understanding of the pathogenesis of HPAI H5N1 PAP-1 (5-(4-Phenoxybutoxy)psoralen) virus infection in chickens and ducks, we examined differences in host gene response to IAV infection between chickens and ducks in vitro (in lung cells) and in vivo. == Materials and.