The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections

Figures & data

Figure 1. Autophagy Signaling During Arbovirus Infection.

There are five possible mechanisms for modulating viral replication which include: a) some arboviruses such as DENV and JEV can use amphisome formation for their entry and replication; b) several arboviruses such as DENV, ZIKV, JEV, CHIKV and TBEV exert diverse mechanisms to induce autophagosome formation to enhance viral replication/translation complexes. DENV is associated with NS4A in up-regulating PI3K-dependent autophagy. CHIKV induces the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition; c) DENV benefits from autophagy activation by using lipid droplets as an energy source for replication; d) Viruses such as DENV-2 and CHIKV can increase their replication by prolonging cell survival and preventing cell death; and d) VSV appears to suppress IFN signaling by conjugated Atg5-Atg12, leading to an effective virus-suppressing immune response [modified from [131]] . DENV: Dengue virus; ZIKV: Zika virus; JEV: Japanese encephalitis virus; CHIKV: Chikungunya virus; TBEV: tick-borne encephalitis virus; VSV: vesicular stomatitis virus.

Table 1. Summary of arbovirus and autophagy pathway.

Reference	Summary of the study	Conclusions
^[147]	Studied Atg5/Beclin-1 knock down model, monitored LC3 lipidation in JEV-infected NT-2 cells	Revealed a direct relationship between autophagy and JEV replication
^[165]	Studied JEV infection	Autophagy process promotes cell survival by delivering damaged mitochondria to lysosomes Autophagy reduces MAVS-IRF3 activation to facilitate virus replication
^[156]	Studied the replication of DENV	DENV replication is cell-specific and it would be limited in monocytes
^[166]		NS4A protein has been characterized as a main component of the DENV2 replication complexes
^[167]		DENV replication/translation is associated with NS4A in up-regulating PI3K-dependent autophagy, and preventing cell death
^[169]		miRNAs help to regulate the proteins that participate in autophagy during persistent infection of mosquito cells with DENV
^[157]	Studied WNV replication	DENV replication was shown to be autophagy independent; however, it still induced autophagy
^[Citation158,Citation159]		supported upregulation of autophagy by WNV
^[160]	mapped the genetic determinants of autophagy regulation in WNV infected cells	Amino acid substitutions in the NS 4A or 4B proteins can modulate the induction of autophagy in WNV-infected cells
^[148]	Studied CHIKV replication	Showed the relation between up-regulation of viral replication and virus-induced autophagy in CHIKV-infected cells
^[Citation148,Citation163]		CHIKV also increases autophagosome formation as a site for aggregation of viral translation/replication complexes
^[168]		Autophagy postpones apoptosis and promotes CHIKV propagation by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition
^[149]	Studied EHDV replication	EHDV induces autophagy, apoptosis and activates c-Jun N-terminal kinase (JNK) and phosphorylates c-Jun which all benefit its replication
^[162]	Studied autophagy in DENV2-infected suckling mice	DENV2-related pathogenesis and survival rate of the suckling mice were enhanced by autophagy, possibly by promoting viral replication
^[152]	Studied DENV-2 and −3 replication	DENV-2 interacts with amphisomes while DENV-3 interacts with both amphisomes and autophagolysosomes
^[171]	Studied VSV replication	Inhibiting IFN production followed by interaction of atg5-atg12 with the CARD of RIG, and MDA5 can promote VSV replication
^[172]	Studied ZIKV replication	Showed a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor, and cellular autophagy in enhancing ZIKV replication in permissive cells
^[173]	Used murine experimental model to infect with Brazillian ZIKV	ZIKV replication is enhanced via induction of autophagy in infected skin fibroblasts. It was demonstrated that Brazilian ZIKV crosses the placenta and causes microcephaly
^[175]	Studied Drosophila brain system	Suggested an essential role for dSTING-dependent autophagy to restrict ZIKV infection and to control neuronal infection
^[Citation176,Citation177]	Studied TBEV replication	TBEV infects and replicates in neural cells inducing neuronal dysfunction, membrane rearrangements and autophagosome formation

CHIKV: Chikungunya virus; DENV: Dengue virus; EHDV: Epizootic hemorrhagic disease virus; JEV: Japanese encephalitis virus; RVFV: Rift Valley fever virus; TBEV: Tick-borne encephalitis virus; VSV: Vesicular stomatitis virus; WNV: West Nile virus; ZIKV: Zika virus.

Figure 2. Apoptosis Signaling During Arbovirus Infection.

Arboviruses exert their effect on apoptosis through different signaling routes. A mechanism for anti-apoptotic activity by these viruses is up-regulation of the PI3K signaling pathway. Another mechanism that viruses can regulate is the initiation of protein 14–3-3 through activation of JNK followed by induction of PKR. CCHFV replication is associated with upregulation of Bax, HRK, PUMA, and Noxa. WNV, JEV and DENV block or delay apoptosis via activating PI3K/Akt signaling. WNV can trigger apoptosis after several rounds of replication through caspases-3 and −12 and p53. JEV triggers ROS-mediated ASK1-ERK/p38 MAPK activation which leads to initiation of apoptosis. JEV may affect Bcl-2 expression to increase anti-apoptotic response. DENV may subvert apoptosis by inhibiting NF-kB. DENV reduces immune responses by activation of p53-dependent apoptosis. RVFV inhibits caspase-8 to regulate pro-apoptotic p53 signaling. The BTV-induced apoptosis involves NF-kB [modified from [131]]. DENV: Dengue virus; ZIKV: Zika virus; WNV: West Nile virus; JEV: Japanese encephalitis virus; CHIKV: Chikungunya virus; CCHFV: Crimean Congo hemorrhagic fever virus; RVFV: Rift Valley fever virus; BTV: bluetongue virus.

Table 2. Summary of arbovirus and apoptosis pathway.

Reference	Summary of the study	Conclusions
^[178]	Studied SINV replication	Apoptosis induced by SINV plays an important role in virus pathogenesis and mortality
^Citation[181–Citation183]		After the entry of SINV into the host cell the dsRNA intermediates are formed, then dsRNA-dependent protein kinase (PKR) recognizes these particles
^[186]	Studied CHIKV replication	The CHIKV triggers the apoptosis to evade immune system and facilitate its dissemination by infecting neighboring cells
^[168]		CHIKV infection can induce apoptotic cell death via intrinsic and extrinsic pathways and facilitates virus release and spread
^[193]	The proteomic analysis in astrocytic cells infected with CHIKV	It showed that Nucleophosmin (NPM1)/B23, a nucleolar multifunctional chaperone, plays a critical role in restricting CHIKV replication
^[194]	Studied mouse models comparing African and Asian strains of CHIKV	Both strains can spread to astrocytes and neurons, however, those with the Asian strain showed increased expression of pro-apoptotic genes and higher mortality
^Citation[187–Citation189]^Citation[190]–Citation192	Studied apoptosis by UV-inactivated viral particles	During CCHFV infection, the over-expression of IL-8 which is an apoptosis inhibitor was independent from apoptotic pathways. CCHFV replication is necessary for apoptosis induction, which was demonstrated by UV-inactivated viral particles
^Citation[190]^[217]	A histopathological analysis about DENV-2 infection on liver of BALB/c mice	Blocking PI3K showed that apoptosis induction might be due to p38 MAPK activation and did not affect JEV and DENV viral particle production Necrosis and apoptosis were clearly noticed as cytopathic effects of DENV-2 infection
^[197]	Studied WNV replication	Akt can directly phosphorylate Bad at position Ser 136 in WNV infected cells
^[Citation190,Citation201]	Studied expression of multiple miRNAs in JEV infection	One miRNA, Hs_154, limits WNV replication by inhibition of two anti-apoptotic proteins like CCCTC binding factor (CTCF) and EGFR-co-amplified and overexpressed protein (ECOP)
^[203]	Studied JEV in mouse neuroblastoma cell line N18	N18 was infected with UV-inactivated JEV (UV-JEV). These virions induced cell death through a ROS-dependent and NF-kB-mediated pathway
^[203]	Studied JEV replication	The initial suppression of UV-JEV-induced cell death, followed by co-infection with active or inactive JEV, demonstrated that JEV may trigger cell survival signaling to modify cellular pathways for timely virus production
^[204]		NS1‘ protein, a neuroinvasiveness factor which is produced by the JEV, was introduced as a caspase substrate; however, using a caspase inhibitor had no effect on virus replication
^[206]		JEV may enhance blood–brain barrier permeability through up-regulation of Bax, Bid, Fas and FasL and down-regulation of IGFBP-2, Bid, p27 and p53
^[207]	Studied JEV in JEV macaque model	The results from a macaque model study indicated neuronal apoptotic death along with the release of pro-inflammatory cytokines which are crucial steps in the pathogenesis of JEV
^[208]	Studied DENV replication	Replication of DENV in monocyte-derived dendritic cells was positively correlated with TNFα and apoptosis
^[210]		Activation of the pro-apoptotic gene caspase-1 played a role in p53-mediated apoptotic pathway and was necessary for up-regulation of different immune response genes following DENV infection
^[210]	microarray analysis
^[Citation199,Citation211]	Studied RVFV replication	NSs and NSm proteins of RVFV delayed apoptosis to efficiently replicate by regulating p53
^[213]		The NSs protein can facilitate viral translation through inhibition of PKR/eIF2α pathway and production of IFN at early stages of infection
^[216]	Studied AHSV replication	AHSV induced apoptosis in mammalian BHK-21 cells through activation of caspase-3
^[218]	Devised anti-CHIKV/DENV dual targeting group I intron	Effectively induced apoptotic cell death following infection, thus preventing viral spread
^[219]	synthesized miRNAs to induce dual DENV-3/CHIKV -resistance phenotypes in the vector mosquito Aedes aegypti	Targeted the conserved DENV and CHIKV sequences, which then led to viral RNA trans-splicing and cell apoptosis
^[172]	Studied on ZIKV infection	ZIKV infection in epidermal keratinocytes caused the appearance of cytoplasmic vacuolation, and the presence of pyknotic nuclei in the stratum granulosum, which is indicative for apoptotic cells
^[220]		South Pacific epidemic strain of ZIKV (PF-25,013–18) can replicate in A549 cells. This infection enhanced Type-I IFNs, ISGs, pro-inflammatory cytokines and delayed mitochondrial apoptosis
^[221]		ZIKV which infects neural progenitor cells in organoid and neurosphere models, activates Toll-like receptor 3 which triggers apoptosis and attenuates neurogenesis
^[222]		Different strains of ZIKV take use of different structural proteins which affect the permissiveness of human epithelial and neuronal cells to this infection
^[223]	Studied on SLEV; its epidemic strain; CbaAr-4005	Suggested probable entrance of SLEV to the CNS from the circulatory system, thus severe disorders induction by this infection within the central nervous system of infected mice
^[224]	Silencing of the A. aegypti anti-apoptotic gene iap1 (Aeiap1) and silencing of initiator caspase gene, Aedronc in adult female A. aegypti mosquitoes	Silencing of the Aeiap1 caused apoptosis in midgut epithelium, and enhanced mosquito mortality and susceptibility to SINV infection. However, silencing of Aedronc protected mosquitoes against mortality and reduced SINV midgut infection
^[225]	Mosquitoes were infected with SINV that expressed a proapoptotic gene, Reaper.	The Reaper-expressing virus showed replication defects in mosquitoes
^[62]	The Aadnr1, a novel gene related to innate immunity and apoptosis in Aedes albopictus, ortholog of dnr1 in Drosophila, was studied in C6/36 mosquito cells	After infection with SINV the transcriptional level of Aadnr1 and subsequently the apoptosis were reduced AaCASPS7 induced caspase-dependent apoptosis in C6/36 cells in Aedes albopictus
^[226]^[227]	Studied an effector caspase; AaCASPS7	AaCASPS7 could be indicated as an apoptotic caspase in arbovirus infection. Thus, apoptosis could be considered as one of the defense pathways in mosquitoes against arbovirus infections, and is probably a factor to determine vector competence
^[228]	Studied mosquito ubiquitin Ub3881	Ub3881 plays role in apoptosis of the mosquito cells during DENV infection. The Ub3881 overexpression targeted DENV envelope protein and reduced virion production. The loss of Ub3881 function reduced the level of apoptosis during DENV infection

AHSV: African horse sickness virus; CCHFV: Crimean Congo hemorrhagic fever virus; CHIKV: Chikungunya virus; DENV: Dengue virus; EHDV: Epizootic hemorrhagic disease virus; JEV: Japanese encephalitis virus; RVFV: Rift Valley fever virus; SINV: Sindbis virus; SLEV: Saint Louis encephalitis virus; TBEV: Tick-borne encephalitis virus; VSV: Vesicular stomatitis virus; WNV: West Nile virus; ZIKV: Zika virus.

Figure 3. UPR Signaling During Arbovirus Infection.

ER stress is enhanced in viral infected cells and activates UPR proteins (e.g. PERK, ATF6, and IRE1). Activated PERK induces ATF4 via phosphorylation of eIF2α, causing attenuation of translation and genes encoding CHOP. Upon IRE1 activation, TRAF2 and XBP mRNA1 splicing are initiated in the cytoplasm, which subsequently leads to regulation of UPR target genes. The degradation of ATF6 is increased through recruitment of ATF6, a UPR sensor, which results in the regulation of protein folding. The consequences of UPR activation are necessary for viral replication and pathogenesis [modified from [131]].

Table 3. Summary of arbovirus and UPR pathway.

Reference	Summary of the study	Conclusions
^[200]	Studied UPR involvement in WNV infection	WNV activates multiple UPR pathways. XBP1 pathway was not necessary for WNV replication; however, ATF6 was degraded by the proteasome and PERK pathway transiently phosphorylated eIF2α and induced the pro-apoptotic protein CHOP. The host mechanism to counteract WNV infection involved activation of CHOP-dependent cell death.
^[Citation200,Citation229]		WNV infection activatied UPR via ATF6/IRE1 pathways.
^[229]		UPR PERK pathway was not activated. The WNV Kunjin strain NS4A and NA4B proteins are potent inducers of UPR. Moreover, sequential removal of hydrophobic domains of NS4A decreased UPR activation. Hydrophobic residues of WNV Kunjin strain NS proteins activate UPR signaling. In contrast, upon infection with WNV, IREI-deficient cells did not illustrate any distinct difference as compared to IREI-positive cells. In the absence of ATF6, other UPR signaling cascades such as PERK and IRE1 pathways could not activate. It was also shown that both ATF6 and IREI are required for STATI phosphorylation, highlighting the necessity of ATF6 for inhibition of innate immune response.
^[232]	Studied UPR involvement in JEV and DENV infection	JEV and DENV infection activated XBP1 pathway in neuoroblastoma N18 cells. Applying small interfering RNA to reduce XBP1 had no effect on cellular susceptibility to the two viruses but enhanced the cellular apoptosis. Both JEV and DENV trigger the XBP1 signaling pathway.
^[231]	Studied UPR involvement in CHIKV and SINV infection	CHIKV specifically activates the ATF6 and IRE1 cascades and suppresses the PERK pathway. CHIKV NSp4 expression in mammalian cells suppresses the eIF2α phosphorylation which regulates the PERK pathway. SINV induced uncontrolled UPR, which was reflected by the failure to synthesis of ER chaperones, followed by increased phosphorylation of eIF2α and activation of CHOP
^[235]	Studied UPR involvement in DENV infection	Showed that A547 ovarian cancer cells infected with DENV elicited the UPR signaling response Different serotypes of DENV have the capacity to modulate different UPR pathways. This unique report showed that the same viruses from the same family could activate different UPR pathways
^[236]	Studied UPR involvement in TBEV infection	TBEV triggers eIF2α phosphorylation. The stress granule component TIA1 binds TBEV RNA which is recruited to perinuclear sites of viral replication to inhibit viral translation.
^[237]		During TBEV infection, IRE1 and ATF6 pathways are triggered
^[238]	Studied UPR involvement in VEEV infection	Following VEEV infection, PERK was activated and the expression of both ATF4 and CHOP (DDIT3) was altered. Expression of EGR1 was also induced in a PERK dependent manner.

CHIKV: Chikungunya virus; DENV: Dengue virus; JEV: Japanese encephalitis virus; RVFV: Rift Valley fever virus; SINV: Sindbis virus; TBEV: Tick-borne encephalitis virus; VEEV: Venezuelan equine encephalitis virus; WNV: West Nile viruss.

Figure 4. Autophagy Signaling During Influenza A Virus Infection.

Influenza A virus (IAV) induces the NLRP3 inflammasome, which causes mitochondrial damage and release of ROS, which prevents the conversion of LC3-II to LC3-I by degrading Atg4 and leads to increased levels of LC3-II. NLRP3 forms an inflammasome complex with ASC and induces the production of inflammatory cytokines. IAV also binds to Beclin1 by the viral M2 protein. It up-regulates the expression of several autophagy-related genes, which can increase autophagic flux. M2 also contains an LC3-interacting region (LIR) which is required for influenza virus subversion of autophagy; this leads to LC3 redistribution to the plasma membrane in infected cells. The complex P-mTORC2/p70S6K blocks lethal autophagy. Autophagosome formation blocks IFN-β and reduces ISG expression [modified from [337]].

Table 4. Summary of influenza virus infection and autophagy pathway.

Reference	Summary of the study	Conclusions
^[Citation124,Citation247]	IAV infection in A549 cells and inhibition of autophagosome/lysosome fusion	Evade of viral antigens presentation by M2 protein independent of M2 proton ion channel function
^[Citation240,Citation250]	Administration of statins and Baf-A1 at low concentration on IAV-infected cells	Confirmed IAV increases autophagosome formation by LC3-II accumulation and inhibits autophagosome maturation/degradation
^[Citation241,Citation251]	Induction of functional autophagy by different IV strains in primary human blood macrophage	Induction of functional autophagy by degradation of the autophagy receptor p62
^[252]	H3N2 infection in both A549 and Ana-1 cells	LC3-II accumulation and autophagy induction a few hpi in both A549 and Ana-1 cells
^[254]	IAV (A/Hong Kong/8/68(H3N2)) infection (the strain sensitive to amantadine)	Blocking autophagy occurred by proton channel activity of M2
^[255]	LC3 relocalisation during IAV infection	Blocking autophagy by proton channel activity of M2, dependency on WD40 CTD of ATG16L1 in non-canonical autophagy pathway
^[256]	M2 ubiquitination-defective mutation (M2-K78R)	Ubiquitination of M2 is not required for blocking late-stage autophagy
^[259]	Studied on effector protein kinase; mTOR	Phosphorylated form of mTOR inhibits autophagy
^[260]	H5N1 infection in mouse embryonic fibroblast (MEF) cells	H5N1 induced autophagy by suppressing phosphorylated mTOR signaling
^[261]	H5N1 infection in human epithelial cells	H5N1 HA glycoprotein was responsible for autophagy induction involving AKT, TSC2 and mTOR
^[263]	Studied lethal autophagy during IAV infection	mTORC2 upregulates p70S6K activity, increases LC3-II formation and viral production by delayed lysosome activity
^[264]	H5N1 infection in human lung epithelial cell lines and mouse lung tissues	The positive feedback between autophagy and NF-kB and p38 MAPK signaling cascades could be an important mechanism contributing to H5N1 lung inflammation
^[267]	Studied ISG expression in IV-infected cells	Induction of autophagy by IAV infection reduces ISG expression by limiting IFN-β expression, which may benefit viral replication
^[268]	Silencing LC3 gene in A549 cells and molecular mechanism underlying the reduction of SOD1 during influenza infection	Supported the critical role of autophagy in the ROS increase in the early phase of flu infection
^[269]	IAV infection and mitochondrial damage	Induction of the NLRP3 inflammasome causing mitochondrial damage and release of ROS and production of IL-1α and IL-18
^[271]	Two cell lines MDCK and MDCK-SIAT1 were transfected with Beclin-1 expression plasmid before and after IV inoculation	The therapeutic approach of autophagy induction inhibited the virus replication at 24 and 48 hr post-infection
^[272]	Studied the role of K27-linked ubiquitination in TRIM23 GTPase function and its ability to activate TBK1-mediated autophagy	Together are key component of selective autophagy for IAV infection. A basis for therapeutics against IAV caused by dysregulation of autophagy
^[273]	designed Kα2-helix peptide derived from vFLIP of Kaposi’s sarcoma-associated herpesvirus (KSHV), Then fused it with the TAT peptide of HIV-1	Autophagy activity at the initial stages of IAV infection which inhibited the binding of FLIP to the E2-like enzyme Atg3 without affecting the interaction of LC3 and Atg3 significant inhibition on lethal doses of H5N1 or H1N1 replication and transmission by destabilizing the viral membrane
^[275]	QD-based SVT technique combined with multi-colour visualization of the transport process of individual viruses	Provided a better understanding of the fundamental relationship between autophagy and virus entry

Figure 5. Apoptosis Signaling During Influenza A Virus Infection.

IAV infection affects apoptosis in early and late infection. In early infection, it has anti-apoptotic effects by decreasing Bax and BAK, but in late infection, it is pro-apoptotic by increasing Bax and BAK, cleavage of PARP-I, truncation of the BID, phosphorylation of BAD and decreasing Bcl-2. Cellular factors P53, miR-29C, TRAIL, CLU and PRPc are involved in IAV infection through the apoptosis pathway. IAV proteins PB1-F2, NP, and NS1 are also involved.

Table 5. Summary of influenza virus infection and apoptosis pathway.

Reference	Summary of the study	Conclusions
^[279]	Used A549 cells and mouse embryonic fibroblasts to study the cross-talk between autophagy and apoptosis in PR8 infection	PR8 infection simultaneously induced autophagy and apoptosis. Cleavage of PARP-1 and truncation of BID increased the ratio of pro-apoptotic protein to anti-apoptotic protein
^[283]	In silico target prediction analysis of complementarity of miR-29c to the 3‘ UTR of BCL2-L2 mRNA in A549 cells	IAV infection affected miR-29c and down-regulated Bcl2-L2 expression, which led to apoptosis promotion
^[280]	Studied IAV infection in mouse embryonic fibroblasts which lack Bax and/or Bak but express functional Bcl-2	Bax induced apoptosis and virus replication, while Bak suppressed apoptosis and viral replication at 24 hpi
^[285]	Studied to define how PI3K/Akt/JNK pathway regulates IV-induced apoptosis.	Bax expression is negatively regulated by the PI3K/Akt/JNK pathway in IAV-infected cells thus inhibit JNK-dependent, Bax-mediated apoptosis
^[278]	PR8 infection induced phosphorylation of BAD	Virus-induced cytopathology and cell death were considerably inhibited in BAD-deficient cells
^[286]	Transcriptome study on apoptosis marker genes in IAV infection	PB1-F2 viral gene was found to be responsible for apoptosis induction in early infection stage
^[Citation288,Citation338]	Studied progress of IAV pathogenesis and transmission	Induction of apoptosis in neutrophils and NK cells
^Citation[289]^[290]^Citation[284]^Citation[292]–Citation294^[295]	-Studied influenza virus NS1 protein	-Caspase-1 activation, fast apoptosis and release of IL-1b and IL-18 -Interaction with tubulin polymerization, arrest of the infected cells in G2/M phase and effect on Bcl-2 phosphorylation -Inhibition of JNK pathway -Activation NF-kB and induction of INF-α and INF-β, induction of SOCS-3 expression and induction of apoptosis -Siva-1 involvement for IAV replication through caspase activation
^[296]	Studied influenza virus (A/California/2009(H1N1) strain) NP protein in A549 cells	Apoptosis induction correlated with NP expression through intrinsic pathway
^[292]^[297]^[256]^[298]^[299] ^[317]	Studied caspase-3 in IAV infection	−2009 pandemic H1N1 A/Beijing/501/2009 induced caspase-3-dependent apoptosis in cell line A549 -Caspase-3-mediated HDAC6 cleavage in IAV-infected MDCK cells caused further damage to the cells -M2-K78R mutant viruses induced apoptosis more than WT viruses -Fucosyltransferase genes in CD4+ effector responses to IAV infection plays a role in maintaining their survival -Prnp0/0 mice showed higher apoptosis level through activated caspase-3 -Se@AM demonstrated caspase-3 activity inhibition and decreasing the level of ROS to trigger AKT pathways
^[300]	Studied caspase-8 in IAV infection	AIVHubei489 (H5N1) showed caspase-8-dependent apoptosis in MDCK
^[301]	Studied caspase-10 in IAV infection in human monocyte-derived macrophages	H5N1 promoted TRAIL and activated caspase-10-depndent apoptosis through activation of BID and intrinsic pathway
^[302]^[303]^[Citation304,Citation305] ^[Citation316,Citation317]	Anti-influenza drugs targets	-(PA)-X, a virulence modulation factor of IAV showed loss of expression and induced apoptosis in A549 cells -Nucleolin (NCL), a novel PA-interacting host protein decreased IAV replication and inflammatory responses -Duck AvIFIT protein, similar to human IFIT2 induces apoptosis by binding influenza NP protein and enhancing the IFN signaling -Attenuation of host ubiquitin ligase RNF43 by P53 and inhibiting IFITM proteins
^[307]	Studied apoptosis in respiratory epithelial cells and PL16T human precancerous respiratory epithelial cells	Onset of apoptosis at early phases of infection and switch from apoptosis to pyroptosis in normal and precancerous cells under type I IFN signaling

Figure 6. UPR Signaling During Influenza A Virus Infection.

Upon IAV infection, BiP is released from UPR proteins (e.g. PERK, ATF6, and IRE1) and facilitates their activation. IRE1 activation results in the splicing of XBP-1 mRNA in the cytoplasm, leading to its nuclear translocation and transcription of UPR target genes. It mediates HA degradation by involvement of three class I α-mannosidases EDEM1, EDEM2, and ERManI. Upon activation of PERK, eIF2a is phosphorylated and blocks protein synthesis. IAV targets eIF2α by inducing P58IPK, then regulates its mRNA translation by PKR-mediated and PERK-dependent mechanisms. ATF6 translocates to the Golgi apparatus where it is cleaved, then moves to the nucleus and targets ER chaperone genes. IAV targets this pathway using MxA.

Table 6. Summary of influenza virus infection and UPR pathway.

Reference	Summary of the study	Conclusions
^[318]	Studied ER stress and UPR in IAV infection in the lung epithelial cells	IAV infection activates IRE1 pathway with subsequent XBP-1 splicing
^[319]	MxA antiviral activity against IAV	Involved in BiP mRNA expression and XBP-1 mRNA processing
^[320]	Studied UPR in murine primary tracheal epithelial cells	IAV infection induced ER-stress via ATF6 and ERp57, but not CHOP, through caspase-12
^[321]	P58^IPK role in IAV infection	-May act synergistically with the UPR-mediated transcriptional activation to help IV relief from both PKR- and PERK-mediated translational repression
^[322]		-Regulates eIF2a, and then regulates IV infection independent of PERK
^[323]	Studied HA glycoprotein degradation	Innate immune induction by HA through ERAD by the critical role of class I α-mannosidases (EDEM1, EDEM2, and ERManI) in initiating HA degradation

Figure 7. Apoptosis Signalling in T-Helper Cells During HIV Infection.

HIV proteins are involved in apoptosis. GP120 attachment to CD4 receptor and CCR5 or CXCR4 can induce the extrinsic pathway in a Fas-dependent manner. GP120 induces Bax expression which activates the intrinsic pathway of apoptosis by the release of cytochrome C (Cyto c) and formation of the apoptosome. Vpr causes cell cycle arrest at the G2 stage. Tat and Nef activate the expression of caspase 8 which changes procaspase 3 to caspase 3 and results in DNA degradation. Tat and Vpr down regulate Bcl2 and BclXL.

Table 7. Summary of HIV infection and autophagy, apoptosis and UPR pathways.

HIV proteins	Autophagy	Apoptosis	UPR
ENV (GP120-GP160)	Inhibition of autophagy in DCs, by activation of mTOR, silencing of LC3 and ATG5	Fas mediated killing, BCl down regulation which activates Bax dependant Mitochondrial pathway	GP120 increases the XBP-1 splicing, increases caspase 3 and caspase 9, increase in BiP and CHOP expression
Tat	Inhibition autophagy by interaction with LAMP2A→ stop autophagosome and lysosome fusion in CD4 + T-cells In glial cells inhibits autophagy by interaction with BAG3	Fas mediated killing, superoxide dismutase inhibition, cyclin dependant kinase activation	Accumulation of GFAP and induction of UPR by all 3 pathways; PERK, IRE1, ATF6 and OASIS. Tat increases the expression of ATF4 for the end of viral latency
Vpr		G2/M arrest → leads to apoptosis with increased BAX (mitochondrial protein) activation→ apoptosis via intrinsic pathway
Nef	Interaction with IRGM ≤ assembly of ULK1/BECLIN-1/ATG6≤ autophagy induction	Apoptosis induction
HIV protease		Induction of apoptosis by cleavage of host proteins

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