*EXTRACELLULAR*400*
*CELL MEMBRANE*200*
*CYTOPLASM*150*
*NUCLEUS*100*
*MITOCHONDRION*100*
*ENDOSOME*100*
*GOLGI APPARATUS*100*
*ENDOPLASMIC RETICULUM*100*
<4>NA [Gy]
<4>M2 [Pa]
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]
X
<3>HA [Gy][Pa]
HA
NA
M2
HA [Gy]
NA [Gy]
<4>NA [Gy]
<3>HA [Gy]
<4>M2
<4>NA [Gy]
<3>HA [Gy][Pa]
<4>M2
T
T
T
Gy
Gy
O
O
O
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]
Pa
<4>M2 [Pa]
T
T
T
<3>HA [Gy]
X
Pa
T
T
T
H+
T
H+
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV assembly)
B
M1:NS2:NP:vRNA
(Viral Genome)
B
SA:SA Receptor
T
TRAF3
IKBKE
TBK1
<2>TLR3:TICAM1:
TRAF3:<2>TBK1:
IKBKE:
B
TLR7
O
TLR7:
TLR7
O
TLR8:
TLR8
IRAK4
IRAK1
CHUK
(IKKa)
B
MYD88:IRAK1:
IRAK4:TRAF6:
TRAF3:CHUK
MYD88
Pro-inflammatory
Cytokines
MAP2K7
TLR8
Ub
MAP3K7 [Ub][A][P]:
MAP3K7IP1[P]:
MAP3K7IP2
MAP3K7[Ub][A]:
MAP3K7IP1:
MAP3K7IP2
B
MAP3K7:
MAP3K7IP1:
MAP3K7IP2
(TAK/TAB complex)
MAP3K7IP2
(TAB2)
MAP3K7IP1
(TAB1)
AP
P
P
P
CHUK:IKBKB:
IKBKG
(IKK)
CHUK:
IKBKB[P][A]:
IKBKG
MAPK8
(JNK)
P
MAPK8[P]
JUN
(AP1)
JUN[P]
P
MAP2K6
MAP2K6[P]
MAPK14[P]
MAPK14
(p38)
MAP2K3
MAP2K3 [P]
OR
P
P
MAP2K4
MAP2K4[P]
P
MAP2K7[P]
OR
O
TLR3
TLR3:TLR3
TICAM1
(TRIF)
TRAF6
RIPK1
(RIP1)
<2>TLR3:TICAM1:
RIPK1:TRADD:
TRAF6:PELI1
B
PELI1
TRADD
Ub
<2>TLR3:TICAM1:
RIPK1[Ub@K63]:TRADD:
TRAF6[Ub@K63]:PELI1
MAP3K7
(TAK1)
ATF2
ATF2[P]
P
OR
NFKB1:RELA:
NFKBIB
NFKB1:RELA
(p50/p65)
D
P
NFKB1:RELA:
NFKBIB[P]
NFKBIB
(IKBB)
/
OR
B
<2>TLR3:TICAM1:
TRAF3
B
<2>TLR3:TICAM1:
APOPTOSIS
IRF3[P]:
IRF7[P]
IRF3[P]:
IRF3[P]
IRF3
IRF7
IRF7[P]
IRF3[P]
B
IRF7[P]:
IRF7[P]
O
O
OR
&
OR
CBP
IFNB1
T
T
T
IRF3[P]:
IRF7[P]
IRF3[P]:
IRF3[P]
IRF7[P]:
IRF7[P]
TL
IFNB1
P
P
JAK1
IFNAR1
TYK2
B
IFNAR2
STAT2 [P]
STAT2
STAT1
STAT1 [P]
B
B
STAT1:
STAT2
IRF9
IFNB1
B
IFNB1:
IFNB1
O
<2>IFNAR1:<2>TYK2:
<2>IFNAR2:<2>JAK1
IFNB1:<2>IFNAR1:<2>TYK2:
IFNB1:<2>IFNAR2:<2>JAK1
P
P
T
AP
TL
TL
TL
OAS1
OAS2
OAS3
STAT1[P]:
STAT2[P]:
IRF9
(ISGF3)
STAT1:
STAT2:
IRF9
(ISGF3)
T
IFNB1
T
PB1-F2 [P]
VDAC1:SLC25A6:
HK2:CKMT1A:
PPID:BZRAP1
(PTPC)
B
PB1-F2:VDAC1:
SLC25A6:HK2:
CKMT1A:PPID:
BZRAP1
(Open PTPC)
CYCS
CASP9[I]
APAF1
CYCS
B
CASP9 [A]
T
Permeabilization
and Swelling
CASP3[A]
X
APAF1:CYCS:
CASP9
(Apoptosome)
XIAP
BAD
BCL2
CASP7[A]
X
CASP8[A]
CASP8[I]
X
CASP2[A]
CASP2[I]
X
OR
tBID
BID
X
CASP6[I]
CASP6[A]
X
AIFM1
ENDOG
AIFM1
T
T
ENDOG
DNA
Fragmentation
GAS2
GAS2[t]
DFFA
DFFA[t][I]
PARP
PARP[t][I]
LMNA
LMNA[t]
CASP3[A]
CASP7[A]
OR
X
X
X
X
Inactive DNA
Repair
Cell Shrinkage
T
T
T
CASP6[A]
T
T
CASP3[I]
CASP7[I]
BAX
BAK1
DIABLO
HTRA2
AIFM1
ENDOG
T
T
HTRA2
DIABLO
T
BAX:BAK1
B
CRADD
(RAIDD)
TRADD
TRAF2
RIPK1
B
TNFRSF1A
TNF
B
TNF:TRADD:TRAF2:FADD:
<3>TNFRSF1A:RIPK1:CRADD
TNF:
<3>TNFRSF1A
OR
MADD
/
OR
Fragmented
DNA
tBID
/
BCL2:BAX[I]:
BAK1[I]
B
BCL2[I]:BAD
B
OR
AX
B
XIAP:CASP9[I]
/
/
/
AKT1
AKT1[P]
P
PIK3R2:PIK3CA
(PI3K)
PIK3R2
(p85beta)
PIK3CA
(p110)
B
PIK3R2:
PIK3CA[A]
A
PIP2
PIP3
C
B
TANK
DDX58[A]
[Ub@K63]
TRIM25
Ub
IFIH1[I]
(MDA5)
B
IKBKE
(IKK-i)
TBK1
TRAF3
DDX58[I]
(RIG-I)
IRF5[P]
IRF5[P]:
IRF5[P]
IRF5
O
P
OR
IFIH1:MAVS:
TRAF3:TANK:
TBK1:
IKBKE
IFIH1:MAVS
B
DDX58:MAVS:
TRAF3:TANK:
TBK1[A]:
IKBKE[A]:
IKBKG
DDX58:MAVS:
TRAF3:TANK:
TBK1:
IKBKE:
IKBKG
B
DDX58:MAVS
B
MAVS
(IPS1)
B
IFIH1[A]
OR
PB2
Viral ssRNA
IFIH1:MAVS:
TRAF3:TANK:
TBK1[A]:
IKBKE[A]
IKBKG
BAK1
T
AP
AP
TL
TL
TL
TL
PRKRA
TL
CASP3
IRF5[P]:
IRF5[P]
DDX58[A]
/
/
X
IL33[t]
IL33
NLRP3[A]:PYCARD:
CARD8:CASP1[I]
AX
NLRP3:PYCARD:
CARD8:CASP1[A]
(INFLAMMASOME)
CARD8
B
IL1B[t]
IL18[t]
X
X
NLRP3[I]
(NALP3)
IL18
IL1B
(proIL-1β)
PYCARD
(ASC)
Low pH
CASP1[I]
PRKRA
EIF2AK2[P]
EIF2S1
EIF2AK2 [P]:
PRKRA
EIF2S1[P]
B
EIF2AK2
TP53[P]
TP53
Inactivation of
Protein Synthesis
P
P
P
EIF2S1
(EIF2alpha)
P
EIF2AK2
(PKR)
AP
EIF2AK2[P]
(PKR)
EIF2S1[P]
OAS1
RNASEL
ATP
2-5A
RNASEL:
ABCE1
D
ABCE1
(RLI)
C
OAS2
OAS3
OR
O
RNASEL:
RNASEL[A]
/
Viral and Host
RNA Degradation
T
T
T
OAS1[A]
OAS2[A]
OAS3[A]
A
A
A
<2>IFNAR1:<2>TYK2:<2>IFNB1:
<2>IFNAR2:<2>JAK1[P]
OR
Inflammation
/
OR
Apoptosis
/
T
TNF
T
TNF
OAS1
OAS2
OAS3
OR
OR
NFkB
Pathway
/
T
IFITM3
IFITM3
T
IFITM3
TL
/
SA:SA Receptor
B
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV)
SA:SA Receptor:
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(Attached IAV)
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
SA:SA Receptor:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV membrane bound)
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV)
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
SA:SA Receptor:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV budding)
Membrane Fission
Virus Budding
AX
TL
NS2 mRNA[5'CAP]
PB1-F2
P
HA
NA
M2
T
T
T
PB1-F2 [P]
T
B
M1
NS2
T
NP
T
T
PB2
PB1
PA
NP
NS2
M1
M1 mRNA[5'CAP]
NS1 mRNA[5'CAP]
HA mRNA[5'CAP]
NA mRNA[5'CAP]
M2 mRNA[5'CAP]
X
T
T
T
T
T
T
T
T
T
T
NS2 mRNA[5'CAP]
M2 mRNA[5'CAP]
PB2 mRNA[5'CAP]
PB1 mRNA[5'CAP]
PA mRNA[5'CAP]
NA mRNA[5'CAP]
M1 mRNA[5'CAP]
NS1 mRNA[5'CAP]
HA mRNA[5'CAP]
NP mRNA[5'CAP]
PB2 mRNA[5'CAP]
PB1 mRNA[5'CAP]
PA mRNA[5'CAP]
NP mRNA[5'CAP]
TL
TL
TL
NP:HA-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:NA-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:NP-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:M-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
TL
TL
TL
TL
NP:PB2-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:PB1-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:PA-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:NS-vRNA:
PB1:PB2:PA:
POLR2A:
Host mRNA[5'CAP]
NP:M-vRNA:
PB1:PB2:PA
NP:PB1-vRNA:
PB1:PB2:PA
NP:NP-vRNA:
PB1:PB2:PA
NP:HA-vRNA:
PB1:PB2:PA
NP:PB2-vRNA:
PB1:PB2:PA
NP:PA-vRNA:
PB1:PB2:PA
NP:NS-vRNA:
PB1:PB2:PA
NP:NA-vRNA:
PB1:PB2:PA
NP:M-vRNA:
PB1:PB2:PA
NP:PB1-vRNA:
PB1:PB2:PA
NP:NP-vRNA:
PB1:PB2:PA
NP:HA-vRNA:
PB1:PB2:PA
NP:PB2-vRNA:
PB1:PB2:PA
NP:PA-vRNA:
PB1:PB2:PA
NP:NS-vRNA:
PB1:PB2:PA
NP:NA-vRNA:
PB1:PB2:PA
X
T
T
T
T
T
T
T
T
B
B
B
B
B
B
B
B
Host mRNA[5'CAP]
M-vRNA:
MCM:POLR2A
PB1-vRNA:
MCM:POLR2A
NP-vRNA:
MCM:POLR2A
HA-vRNA:
MCM:POLR2A
PB2-vRNA:
MCM:POLR2A
PA-vRNA:
MCM:POLR2A
NS-vRNA:
MCM:POLR2A
NA-vRNA:
MCM:POLR2A
TL
TL
TL
TL
TL
TL
TL
TL
HA-cRNA
NS-cRNA
NA-cRNA
M-cRNA
PB2-cRNA
PB1-cRNA
PA-cRNA
NP-cRNA
HA-vRNA
NP:HA-cRNA
NS-vRNA
NA-vRNA
M-vRNA
PB2-vRNA
PB1-vRNA
PA-vRNA
NP-vRNA
NP:NA-cRNA
NP:M-cRNA
NP:NS-cRNA
NP:PB2-cRNA
NP:PB1-cRNA
NP:PA-cRNA
NP:NP-cRNA
NP:HA-vRNA
NP:NA-vRNA
NP:M-vRNA
NP:NS-vRNA
NP:PB2-vRNA
NP:PB1-vRNA
NP:PA-vRNA
NP:NP-vRNA
NP:M-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:PB1-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:NP-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:HA-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:PB2-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:PA-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:NS-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:NA-vRNA:
PB1:PB2:PA
(vRNP Progeny)
NP:M-vRNA:
PB1:PB2:PA:
M1
NP:PB1-vRNA:
PB1:PB2:PA:
M1
NP:NP-vRNA:
PB1:PB2:PA:
M1
NP:HA-vRNA:
PB1:PB2:PA:
M1
NP:PB2-vRNA:
PB1:PB2:PA:
M1
NP:PA-vRNA:
PB1:PB2:PA:
M1
NP:NS-vRNA:
PB1:PB2:PA:
M1
NP:NA-vRNA:
PB1:PB2:PA:
M1
POLR2A
MCM complex
B
B
B
B
B
B
B
B
POLR2A:
Host mRNA[5'CAP]
NP:HA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:M-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PB2-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PB1-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NS-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NP-vRNA:
PB1:PB2:PA:
M1:NS2
T
T
T
T
T
T
T
NP:HA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:M-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PB2-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PB1-vRNA:
PB1:PB2:PA:
M1:NS2
NP:PA-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NS-vRNA:
PB1:PB2:PA:
M1:NS2
NP:NP-vRNA:
PB1:PB2:PA:
M1:NS2
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
TL
TL
TL
TL
TL
TL
TL
TL
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
MACROPINOCYTOSIS
CLATHRIN MEDIATED
ENDOCYTOSIS
<4>M2 [Pa]
<4>NA [Gy]
H+
T
M1
NS2
SA:SA Receptor:
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(Endocytosed IAV)
H+
/
/
/
/
H+
SA:SA Receptor:
<3>HA1 [Gy][Pa]:
<3>HA2 [Gy][Pa]:
<4>NA[Gy]:<4>M2[Gy]:
M1:NS2:NP:vRNA:
PB1:PB2:PA
(IAV Low pH)
vATPase
D
<3>HA2 [Gy][Pa][A]
NP:M-vRNA:
PB1:PB2:PA
NP:PB1-vRNA:
PB1:PB2:PA
NP:NP-vRNA:
PB1:PB2:PA
NP:HA-vRNA:
PB1:PB2:PA
NP:PB2-vRNA:
PB1:PB2:PA
NP:PA-vRNA:
PB1:PB2:PA
NP:NS-vRNA:
PB1:PB2:PA
NP:NA-vRNA:
PB1:PB2:PA
Fusion of
Virus and Endosome
membranes
& vRNP release
T
T
T
T
T
T
T
T
Viral ssRNA
NS1
PB1:PB2:PA
B
PB2
PB1
PA
T
T
T
Viral RNA [3P]
Viral RNA [3P]
B
TL
TL
TL
TL
TL
TL
TL
TL
TL
TL
SOCS3
SOCS3
T
SOCS3
TL
TP53[P]
OR
OR
Host Translation
complex
(Inactivated)
/
/
CXCL11
RIPK1
Intracellular Signal Transduction
T-Cell Activation
TL
MXA
MX1
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
1000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
1000
1000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
10000
1-2,0;3-4,10;5-500,0
10000
1000
33
33
33
33
33
33
33
33
1000
1000
55
70
85
55
55
55
70
55
1000
1000
0.18
0.20
0.5
0.4
0.35
260
260
260
200
200
400
520
200
0.05
0.05
0.05
10000
8
8
1000
1000
1000
10000
1-10,1000;11-500,0