Table 4.

Virulence determinants identified in H9 influenza A viruses (IAVs)

			Virulence
Gene	Protein	Residue	Lower	Higher	Effect	Reference(s)
1	PB2	147	M	L	Increased virulence in mice	Wang et al. 2012; Naguib et al. 2015; Mosaad et al. 2018
		250	V	G	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015; Mosaad et al. 2018
		253	D	N	Increase replication and transmission in ferrets	Yamada et al. 2010; Mok et al. 2011; Kimble et al. 2014
		292	I	V	Increased virulence in mice	Gao et al. 2019; Suttie et al. 2019
		404	F	L	Increased virulence in mice	Liu et al. 2014
		504	I	V	Increased virulence in mice	Kandeil et al. 2014, 2019; Naguib et al. 2015
		588	T	I	Increased virulence in mice	Xiao et al. 2016; Suttie et al. 2019
			A	V	Higher polymerase activity; efficient replication in mammalian and avian cells; increased virulence in mice	Xiao et al. 2016; Lloren et al. 2017
		591	Q	K/R	Increased virulence in mice	Mok et al. 2011; Suttie et al. 2019
		627	E	V/K	Increased virulence in mice	Wang et al. 2012; Li et al. 2014; Naguib et al. 2015; Suttie et al. 2019
		701	D	N	Increase replication and transmission in ferrets; increase virulence in mice and chickens	Yamada et al. 2010; Kandeil et al. 2014; Kimble et al. 2014; Naguib et al. 2015
		714	S	R	Increased virulence in mice	Sediri et al. 2016; Suttie et al. 2019
2	PB1	317	M/V	I	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		577	K	E	Increased virulence in mice	Kamiki et al. 2018; Suttie et al. 2019
	PB1-F2	66	N	S	Increased virulence in mice	Conenello et al. 2011; Naguib et al. 2015
3	PA	127	I	V	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		356	K	R	Increased virulence in mice	Xu et al. 2016; Suttie et al. 2019
		550	I	L	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		672	F	L	Increase replication, transmission and pathogenicity in chickens	Zhong et al. 2014; Naguib et al. 2015; Mosaad et al. 2018
		PA-X	Δ	PA-X	Virulence in mice	Gao et al. 2015a,b; Suttie et al. 2019
4	HA	148	D	N	Increased virulence in chickens and mice	Jin et al. 2019; Suttie et al. 2019
		166	N	S	Increased virulence in mice	Park et al. 2015
		188	N	T	Increase replication and transmission in ferrets	Kaverin et al. 2004
6	NA	45–46		Δ	Increased virulence in chickens	Guo et al. 2000; Liu et al. 2014
		62–64		Δ	Increased virulence in chickens	Guo et al. 2000; Lin et al. 2014; Liu et al. 2014
		119	E	D	Reduced susceptibility to zanamivir	Kode et al. 2019; Suttie et al. 2019
7	M2	31	S	N/G	Increased resistance to amantadine and rimantadine	Ilyushina et al. 2005; Suttie et al. 2019
		64	P	S/A/F	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		69	L	P	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
8	NS1	230–237 Elongation			Increased replication and inflammatory cytokine production in chickens	Kong et al. 2015; Suttie et al. 2019
		2	D	N	Increase replication and transmission in ferrets	Kimble et al. 2014
		42	A/P	S	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015; Yu et al. 2016
		103	F	L	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		106	I	M	Increase virulence in mice and chickens	Ayllon et al. 2014; Kandeil et al. 2014; Naguib et al. 2015
		189	D/G	N	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
	NS2/NEP	31	M	I	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015
		56	H/L	Y	Increase replication, transmission and pathogenicity in chickens	Naguib et al. 2015

All HA positions follow the H9 numbering. All the other genes follow original numbering as stated in the references. Not necessarily tested in H9 IAV backgrounds.