Pathogenicity and virulence of influenza

Figures & data

Figure 1. Illustration of influenza virion components, genomic organization, and viral genes. (a) Influenza virus is an enveloped RNA virus, which has 3 envelope proteins (HA, NA, and M2) on the viral membrane, an M1-formed matrix layer, and eight vRnps. (b) Each vRNP consists of one vRNA segment wrapped with NP and associated with polymerase complex PB2/PB1/PA. (c) Each vRNA segment encodes 1–3 genes, through alternative splicing (NS2/NEP and M2) and frameshifting (such as PA-X and PB1-F2). Accessory proteins expressed through frameshifting are shown as filled dark green bars/boxes.

Figure 2. Influenza virus evolution. Almost all IAV subtypes (H1 to H16, N1 to N9) have natural hosts in water birds, of which some have established infections in other species, such as H1N1, H2N2, and H3N2 in humans and pigs. Human influenza viruses have changed over the years mainly due to the emergence of four pandemic flu viruses. Currently, circulating influenza viruses include two IAV subtypes H1N1 and H3N2, and two IBV lineages (B/Yamagata and B/Victoria). Some animal IAVs, particularly bird and swine flu, can occasionally spill over to cause zoonotic infections in humans. In recent years, avian H5 and H7 viruses caused human infections with a high case fatality rate.

Table 1. Molecular markers associated with virulence and pathogenicity of influenza virus. HA substations are based on the H3 numbering system[97].

Genes	Subtype	Position	Molecular markers and functions	References
HA	H5	83, 128, 197, 496	K83, P128, K197, K496 work in two or more combinations to increase binding to α2–6 glycans	[34]
	H7	104	N104K increases affinity to both α2,3- and α2,6-linked SA	[35]
	H5	110	H110Y increases thermostability and pH stability, adaptive mutation for airborne transmission	[32,36,37]
	H5	126	S121N enables H5N1 virus binding to both a2–3 and α2–6 glycans	[38]
	H5, H7	138	L129V/A138V increase H5N1 binding to α2–6 glycans, A138V decreases α2–3 binding; A138-V186-P221 increased H7N9 binding to human-type receptors	[39–42]
	H5	143	G143R increases H5N1 virus binding to α2–6 glycans	[34]
	H5	158	N158D leads to loss of N-glycosylation site, increases human-type receptor binding, adaptive mutation for airborne transmission	[31,36,38,43]
	H5	160	T160A increases overall virus binding to both α2,3-SA and α2,6-SA, adaptive mutation for airborne transmission	[28,32]
	H7	186	A138-V186-P221 increase H7N9 binding to human-type receptors, V186G/K-K193T-G228S or V186N-N224K-G228S can switch the receptor specificity of the H7N9 HA from avian- to human-type	[39,44,45]
	H9	187, 227	T187P-M227L increase H9N2binding to human-type receptors, enhanced replication and virulence in mice	[46]
	H1	190	D190-D225 determines α − 2,6 binding specificity of H1N1. E190-G225 switched to α − 2,3-binding	[47–49]
	H7	193	V186G/K-K193T-G228S can switch the receptor specificity of the H7N9 HA from avian- to human-type	[44,45]
	H5	196	Q196R/H increases H5N1 virus binding to α2–6 glycans	[29,34,50]
	H5	214	V214I increases H5N1 virus binding to α2–6 glycans	[50]
	H7	221	A138-V186-P221 increase H7N9 binding to human-type receptors	[39]
	H5, H7	224	V186N-N224K-G228S can switch the receptor specificity of the H7N9 HA from avian- to human-type, N224K increased H5N1 binding to human-type receptors, adaptive mutation for airborne transmission of H5N1	[31,35,44]
	H1	225	D190-D225 determine α − 2,6 binding specificity of H1N1. E190-G225 switched to α − 2,3-binding	[47,48,51]
	H2, H3, H5, H7, H9, H10, H15	226	Q226L-G228S change H2 and H3 receptor binding specificity from α2–3 to α2–6 glycans; Q226L increases HA binding to human-type receptors of various subtypes	[52,53,5439,55–58]
	H5, H9	227	S227N increases H5N1 virus binding to α − 2,6 glycans, T187P-M227L increase H9N2 binding to human-type receptors	[29,38]
	H2, H3, H5, H7, H9, H10, H15	228	Q226L-G228S change H2 and H3 receptor binding specificity from α2–3 to α2–6 glycans; G228S increased virus binding to α − 2,6 glycans	[39,52,53,55–58]
	H5	318	T318I increases HA stability, adaptive mutation for airborne transmission	[28,32,36,37,59]
	H5, H7	329	Insertion of multi-basic residues expands tissue tropism in birds and generates HPAIVs	[60,61]
	H5, H7	58 (HA2)	K58I increases thermostability and pH stability	[35,62,63]
PB2	H5N1	9	D9N enhances viral polymerase activity, inhibits MAVS to suppress IFN-I production	[64,65]
PB2	H1N1	271	T271A enhances polymerase activity in human cells	[66]
PB2	H7N9, H5N1, H3N2	526	K526R cooperates with E627K to synergistically increase viral polymerase activity	[67]
PB2		627	E627K is a mammalian-adaptive mutation, increases avian virus replication in mammalian cells	[68,69]
PB2	H9N2	526, 543, 627, 655	E627V-E543D-A655V-K526R mutations acted cooperatively to increase viral polymerase activity in human cells	[70]
PB2		701	D701N is a mammalian-adaptive mutation, increases avian virus replication in mammalian cells, improved binding of PB2 to importin protein in mammalian cells	[69,71]
PB2	H7N7	714	S714R is a mouse-adapted mutation, enhances viral polymerase activity in mammalian cells	[72]
PB1	H5N1	3	D3V enhances viral polymerase activity	[73]
PB1	H5N1	99	H99Y increases viral polymerase activity, mammalian-adaptive mutation	[28,32]
PB1	H1N1, H5N1, H7N9	612	K612 SUMOylation is critical for the viral RNA binding activity of PB1, essential for viral pathogenesis and transmission	[74]
PB1	H5N1	622	D622G enhances viral polymerase activity, virulence in mice	[73,75]
PA	H7N9	37	S37A increases polymerase activity in human cells	[76]
PA	H7N7	63	V63I increases viral polymerase activity, viral replication and virulence in mammalian cells	[77]
PA	H1N1	85, 186, 336	85I − 186S −336 M enhances avian virus polymerase activity in mammalian cells	[78]
PA	H5N1	224, 383	P224-D383 synergistically enhance viral replication in mammalian cells	[79]
PA	H7N9	383	N383D increases polymerase activity in human cells	[76]
PA	H5N6	343	A343T cooperates with E627K to synergistically increase viral polymerase activity in mammalian cells	[40]
PA	H9N2	356	K356R cooperates with E627K to synergistically increase viral polymerase activity	[67,80]
PA	H1N1	552	T552S increases avian virus polymerase activity in mammalian cells	[81]
NP	H7N9, H9N2	41	V41 enhances viral polymerase activity	[82]
NP	H7N9, H9N2	210	E210D enhances viral polymerase activity	[82]
NP	H7N7	319	N319K is mouse-adapted mutation, improves binding of NP to importin protein in mammalian cells	[72,83]
NP	H1N1	357	Q357K enhances viral replication, mammalian-adaptive mutation	[84]
M1	H5N1	30, 215	N30D-T215A increases viral replication and viral virulence in mice	[114]
M1	H9N1	37	T37A abolishes the phosphorylation site to stabilize the M1 protein, increases viral replication in mammalian species	[116]
NS1	H5N1	42	P42S increases viral virulence in mice by preventing the dsRNA-mediated activation of the NF-κB and IRF − 3 pathways	[119]
NS1	H7N9	106	I106M increases viral virulence in mice by enhanced CPSF30 binding	[120,121]
PA-X			host- and strain-specific role in viral virulence and pathogenicity	[118]
PB1-F2			host- and strain-specific role in viral virulence and pathogenicity	[85,131]
PB1-F2	H5N1	66	N66S increases viral pathogenicity in mice	[94]

Figure 3. Pro-viral host factors and host signalling pathways important for influenza viral replication. Host factors and cellular signalling pathways are hijacked by the influenza virus to promote viral replication at different steps of the viral life cycle. Host factors are listed inside light green boxes next to the specific step of viral replication. Receptor tyrosine kinases (EGFR, c-Met, TrkA) on plasma membranes are activated by influenza viral infection and function to promote viral replication. EGFR, c-Met, and PLC-γ1 enhance viral uptake. TrkA signalling is important for several steps of the viral life cycle: viral RNA synthesis, vRNP nuclear export, and viral budding and release. NF-κB signalling enhances viral RNA synthesis and induces the expression of proinflammatory genes. PI3K/Akt and Raf/MEK/ERK pathways also strongly increase viral replication.

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