The constellation of genes coding for viral RNA polymerase complex (PB1, PB2, PA and NP) appears to have an important role in virulence. When the complete set of these genes was derived from one or the other avian parent virus, the reassortant was, in general, pathogenic. In contrast, all non-pathogenic reassortants had a mixed polymerase complex. This was the case regardless of whether these genes ultimately came from pathogenic or non-pathogenic strains (Rott et al. 1979; Giesendorf et al. 1986). Reassortment, even between highly pathogenic strains may lead to pathogenic as well non-pathogenic reassortants (Rott et al. 1979). By contrast, virulent reassortants can be derived following mixed infection with two avirulent parents. The host range restriction and virulence of influenza viruses is significantly affected, even in H5 and H7 viruses, by the type of amino acid present at 627 position of PB2 protein. The LPAI and HPAI viruses contain glutamic acid and lysine, respectively, at 627 position of PB2 protein. The presence of glutamic acid at this position in H5 or H7 makes them less virulent (Almond 1977; Subbarao et al. 1993; Fouchier, et al. 2004; Hatta et al. 2001; Li et al. 2004; Puthavathana et al. 2005). The efficiency of growth influenza viruses in mammalian cells is enhanced by the presence of lysine at 627 position of PB2 protein (Crescenzo-Chaigne et al. 2002; Shinya et al. 2004). The PB2 protein of an HPAI virus strain A/chicken/Yamaguchi/7/2004 (H5N1) has been found to determine its replication capability in pigs (Manzoor et al. 2009). The PB1-F2 protein of influenza A virus plays a role in viral pathogenesis in mice (Zamarin et al. 2006) but pathogenesis of H1N1 seasonal influenza virus was not affected by PB1-F2 protein (Herfst et al. 2010; Meunier and von Messling 2012). The pathophysiology and severity of influenza virus disease was found to be contributed by PB1-F2 protein induced activation of the NLRP3 inflammasome (McAuley et al. 2013). The interaction of C-terminal region of PB2 with importin is involved in host adaptation of influenza viruses (Boivin and Hart 2011; Bortz et al. 2011). The viral polymerase helps in the adaptation of an avian influenza virus to mammalian host (Gabriel et al. 2005). It has been observed that adaptive mutations that result in enhanced polymerase activity can increase the virulence of influenza A virus in mice (Rolling et al. 2009). The NA protein has also been reported to have a role in host range restriction and pathogenicity (Goto and Kawaoka 1998). The NS1 protein may affect the pathogenicity of influenza viruses due to the differences in their abilities to counteract the effects of cellular interferon or induction of high levels of proinflammatory cytokines (Cheung et al. 2002; Seo et al. 2002; 2004; Lipatov et al. 2005; Soubies et al. 2010; Zielecki et al. 2010; Mukherjee et al. 2012; Rajsbaum et al. 2012). Recently, studies were conducted on the activation of the inflammasome by influenza-A-virus- infected lung epithelial cells. The NS1 protein that originated from an HPAI virus had enhanced interaction with RIG-I resulting in inhibition of type I IFN and IL-1β responses compared to the LPAI virus strains in lung epithelial cells and in ferrets (Pothlichet et al. 2013). The pathogenicity of a HPAI virus A/whooper swan/Mongolia/3/2005 (H5N1) in ducks was shown to correlate with the PB2, PA, HA, NP and NS genes (Song et al. 2011; Kajihara et al. 2013). The viral NP protein plays an important role in Mx sensitivity determination of influenza A viruses (Zimmermann et al. 2011). The role of the host genetic determinants and various host factors in the pathogenicity of influenza viruses has been reported (Lin and Brass 2013; Tran et al. 2013; Rodrigue-Gervais et al. 2014). A potential role for dendritic cells (DC) has been speculated in HPAI pathogenesis based on the observations that infection of monkeys with influenza H5N1 was associated with recruitment, activation and apoptosis of DC in lung-draining lymph (Soloff et al. 2014).

Currently, the H7N9 is producing havoc in humans and raising a lot of concern. By 6 August 2013, novel influenza viruses of the H7N9 subtype had infected 132 humans and killed 43 people in 10 provinces on mainland of China, and one imported case was also found in Taiwan. The HA and NA genes of this virus strain probably originated from Eurasian avian influenza viruses; the remaining genes are closely related to avian H9N2 influenza viruses (Chang et al. 2013; Gao et al. 2013; Hu et al. 2013; Kageyama et al. 2013; Liu et al. 2013; Lamb 2013; Morens et al. 2013; WHO 2013). The tropism (Belser and Tumpey 2013), and human-to-human transmission of H7N9 (Rudge and Coker 2013) have been described. The mutations in the PA gene (Yamayoshi et al. 2014) or PB2 gene (Mok et al. 2014) can affect its virulence. Various studies were conducted with this virus in mouse and ferret model (Belser et al. 2013a; Xu et al. 2013). The H7N9 virus is able to infect epithelial cells in the human upper and lower respiratory tracts as well as alveolar type II pneumonocytes. The pathogenesis in humans has partly been attributed to increased levels of chemokines and cytokines such as IP-10, MIG, MIP-1β, MCP-1, IL-6, IL-8 IL-2 and IFN-α (Chi et al. 2013; Zhou et al. 2013). The characteristics, diagnosis and measures for the prevention and control of this H7N9 virus have been reported (ECDC 2013; WHO 2013). The glycan-receptor binding of influenza A virus H7 haemagglutinin has been described (Srinivasan et al. 2013). Ocular tropism of the H7N3 HPAI virus was responsible for the conjunctivitis in human (Belser et al. 2013b).

The possibility and probability of a viral strain to emerge as a new influenza subtype in humans and act as a potentially pandemic influenza virus will depend on (i) its capacity to produce disease in a susceptible host following efficient infection and replication in it (i.e. its pathogenicity) and (ii) to a larger extent on its capability for efficient spread from infected to non-infected hosts (i.e. its transmissibility). The molecular parameters influencing the transmissibility of influenza virus has not been resolved so far and remains an underexplored area.