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Apoptosis, autophagy and unfolded protein response pathways in Arbovirus replication and pathogenesis.

Iranpour M, Moghadam AR, Yazdi M, Ande SR, Alizadeh J, Wiechec E, Lindsay R, Drebot M, Coombs KM, Ghavami S - Expert Rev Mol Med (2016)

Bottom Line: Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern.The arbovirus infection and replication processes are complex, and many factors are involved in their regulation.In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes.

View Article: PubMed Central - PubMed

Affiliation: Zoonotic Diseases and Special Pathogens,National Microbiology Laboratory,Public Health Agency of Canada,1015 Arlington St.,Winnipeg,Manitoba,Canada.

ABSTRACT
Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

No MeSH data available.


Related in: MedlinePlus

Graphic representation of apoptosis and viral replication. Viral infection, in general, can induce both intrinsic and extrinsic apoptotic pathways. Viruses like CHIKV, CCHFV and RVFV initiate extrinsic signals through cell death ligands (e.g. FasL, APO-2L, TRAIL, TNF), causing caspases-8 activation which then triggers caspases-3, -6 and -7). AHSV and WNV directly trigger caspase 3; however, CHIKV targets caspase 9. DENV and WNV affect the intrinsic pathway of apoptosis through stimulation of P53. Once P53 is activated, mitochondria-dependent apoptosis can be activated. Viral infection can also induce PKR and this kinase can affect eIF2a, resulting in activation of effector caspases and initiation of apoptosis. Viruses can also have anti-apoptotic activity. DENV, WNV and JEV trigger survival signalling through PI3K-AKT signalling pathway. PKR can be initiated by Sindbis virus which leads to inhibition of cellular translation through eIF2a phosphorylation, suppressing Mcl-1 biosynthesis. Sindbis virus can regulate 14-3-3 through activation of JNK followed by induction of PKR (for other details see text). AHSV, African horse sickness virus; CHIKV, Chikungunya virus; CCHF, Crimean–Congo haemorrhagic fever virus; DENV, Dengue virus; FasL, Fas (Apo-1/CD95) ligand; JEV, Japanese encephalitis virus; JNK, c-Jun N-terminal kinases; TNF, tumour necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; PKR, (dsRNA)-activated protein kinase; RVFV, Rift valley fever virus; WNV, West Nile virus.
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fig07: Graphic representation of apoptosis and viral replication. Viral infection, in general, can induce both intrinsic and extrinsic apoptotic pathways. Viruses like CHIKV, CCHFV and RVFV initiate extrinsic signals through cell death ligands (e.g. FasL, APO-2L, TRAIL, TNF), causing caspases-8 activation which then triggers caspases-3, -6 and -7). AHSV and WNV directly trigger caspase 3; however, CHIKV targets caspase 9. DENV and WNV affect the intrinsic pathway of apoptosis through stimulation of P53. Once P53 is activated, mitochondria-dependent apoptosis can be activated. Viral infection can also induce PKR and this kinase can affect eIF2a, resulting in activation of effector caspases and initiation of apoptosis. Viruses can also have anti-apoptotic activity. DENV, WNV and JEV trigger survival signalling through PI3K-AKT signalling pathway. PKR can be initiated by Sindbis virus which leads to inhibition of cellular translation through eIF2a phosphorylation, suppressing Mcl-1 biosynthesis. Sindbis virus can regulate 14-3-3 through activation of JNK followed by induction of PKR (for other details see text). AHSV, African horse sickness virus; CHIKV, Chikungunya virus; CCHF, Crimean–Congo haemorrhagic fever virus; DENV, Dengue virus; FasL, Fas (Apo-1/CD95) ligand; JEV, Japanese encephalitis virus; JNK, c-Jun N-terminal kinases; TNF, tumour necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; PKR, (dsRNA)-activated protein kinase; RVFV, Rift valley fever virus; WNV, West Nile virus.

Mentions: To date, several investigations have been carried out on the importance of apoptosis in different virus infections, pathogenesis and replication, but many issues are still unclear and under debate (Refs 212, 213, 214). As summarised in Figure 7, a number of arboviruses such as Sindbis virus, WNV and JEV seem to use apoptosis as a virulence factor to promote their own pathogenesis (215, 216, 217). Each of these viruses has specific targets and biochemical-induced mechanisms during virus-induced programmed cell death. The observations suggest that Sindbis virus-induced apoptosis plays an important role in Sindbis virus pathogenesis and mortality (Ref. 215). After entry of Sindbis virus into the host cell and subsequent formation of Sindbis virus double-stranded RNA intermediates, dsRNA-dependent protein kinase (PKR) recognises these particles (Refs 218, 219, 220). PKR blocks cellular translation through eIF2a phosphorylation, which later can inhibit Mcl-1 (anti-apoptotic Bcl2 family protein) biosynthesis (Ref. 221). PKR also controls c-Jun N-terminal kinases (JNK) through IRS1 phosphorylation and later activates 14-3-3 (Ref. 222). Thus, 14-3-3 affects the accessibility of substrates (e.g., Bad) to kinases and serves to localise kinases to their substrates, thereby leading to release of Bad and disruption of the complex between anti-apoptotic Bcl2 family proteins, Bcl-xl and Bak. Both Bad and Bik can displace Bak from Mcl-1, which results in Bak oligomerization and cytochrome c release, and subsequent induction of apoptosis (Ref. 222). CHIKV triggers the apoptosis machinery and uses apoptotic blebs to evade immune responses and facilitate its dissemination by infecting neighboring cells (Ref. 223). CHIKV infection can induce apoptotic cell death via at least two apoptotic pathways: the intrinsic pathway, which has been reported to be involved in virus replication and results in activation of caspase-9, and the extracellular pathway, which is dependent on the induction of cell surface or soluble death effector ligands that activate caspase-8. Thus, both pathways activate caspase-3 and finally induce cell death, and this facilitates virus release and spread (Ref. 211). The replication of Crimean-Congo haemorrhagic fever virus (CCHFV), an arbovirus from the family Bunyaviridae, is associated with the death receptor pathway of apoptosis. Up-regulation of pro-apoptotic proteins (i.e. BAX and HRK) and novel components of the ER stress-induced apoptotic pathways (i.e. PUMA and Noxa) have also been shown in a CCHFV-infected hepatocyte cell line, which suggests a link between CCHFV replication, ER stress and apoptotic pathways. Notably, differential high levels of transcription factors, such as CHOP, which are activated through ER stress, are present in hepatocytes following CCHFV replication (Ref. 224). In this study, it was shown that the over-expression of IL-8, an apoptosis inhibitor, during CCHFV infection was independent from apoptotic pathways. However, in other studies, a positive correlation was detected between IL-8 induction and DENV infection (Refs 224, 225, 226). In contrast to Sindbis virus, CHIKV and CCHFV replication in infected cells have been proposed to be necessary for apoptosis induction, as demonstrated by the use of UV-inactivated viral particles (Refs 227, 228, 229). The replication of Flaviviruses (e.g. WNV, JEV and DENV) can be limited by virus-induced programmed cell death at the early stage of virus infection. These viruses might block or delay apoptosis via activating several cell survival pathways, such as PI3K/Akt signalling, to improve their replication rate (Refs 227, 230). Blocking PI3K (using LY294002 and wortmannin) showed that the induction of apoptosis might be a result of p38 MAPK activation and did not affect JEV and DENV viral particle production (Ref. 227). In 2001, del Carmen Parquet et al. demonstrated that WNV-induced cytopathic effect was caused during induction of apoptosis and that viral replication is an essential event for virus-induced cell death (Ref. 231). WNV capsid protein has an anti-apoptotic role, ensuring that it can block or delay apoptosis by suppression of the phosphatidylinositol (PI) 3-kinase-dependent process at the early stage of infection (Ref. 230). In addition, Akt is a downstream target of PI3-kinase and can directly phosphorylate the pro-apoptotic protein Bad at position Ser 136 (Ref. 232). WNV can initiate apoptosis through caspases-3 and -12 and p53 after several rounds of replication and it is noteworthy that initial viral dose exerts an influence on kinetics of WNV-induced cell death (Refs 228, 233, 234, 235). After some RNA virus infections, expression of multiple miRNAs in host cells might have either a positive or negative effect on virus replication. One such cellular miRNA, Hs_154, limits WNV replication by inducing apoptosis through inhibition of two anti-apoptotic proteins like CCCTC binding factor (CTCF) and EGFR-co-amplified and overexpressed protein (ECOP) (Refs 227, 236). JEV, an RNA virus, may induce ROS-mediated ASK1-ERK/p38 MAPK activation and thus lead to initiation of apoptosis (Ref. 237). In mouse neuroblastoma cells (line N18) infected with ultraviolet-inactivated JEV (UV-JEV), replication-incompetent JEV virions induced cell death through a ROS-dependent and NF-kB-mediated pathway (Ref. 238). Initial suppression of UV-JEV-induced cell death, followed by co-infection with active or inactive JEV, showed that JEV may trigger cell survival signalling to modify the cell environment for timely virus production (Ref. 238). NS1′ protein, a neuroinvasiveness factor that is only produced by the JEV serogroup of Flaviviruses during their replication, was introduced as a caspase substrate in virus-induced apoptosis; however, use of a caspase inhibitor had no effect on virus replication (Ref. 239). Empirical evidence showed that JEV can affect Bcl-2 expression to increase anti-apoptotic response rather than anti-viral effect to enhance virus persistence and reach equilibrium between replication and cell death (Ref. 240).Figure 7.


Apoptosis, autophagy and unfolded protein response pathways in Arbovirus replication and pathogenesis.

Iranpour M, Moghadam AR, Yazdi M, Ande SR, Alizadeh J, Wiechec E, Lindsay R, Drebot M, Coombs KM, Ghavami S - Expert Rev Mol Med (2016)

Graphic representation of apoptosis and viral replication. Viral infection, in general, can induce both intrinsic and extrinsic apoptotic pathways. Viruses like CHIKV, CCHFV and RVFV initiate extrinsic signals through cell death ligands (e.g. FasL, APO-2L, TRAIL, TNF), causing caspases-8 activation which then triggers caspases-3, -6 and -7). AHSV and WNV directly trigger caspase 3; however, CHIKV targets caspase 9. DENV and WNV affect the intrinsic pathway of apoptosis through stimulation of P53. Once P53 is activated, mitochondria-dependent apoptosis can be activated. Viral infection can also induce PKR and this kinase can affect eIF2a, resulting in activation of effector caspases and initiation of apoptosis. Viruses can also have anti-apoptotic activity. DENV, WNV and JEV trigger survival signalling through PI3K-AKT signalling pathway. PKR can be initiated by Sindbis virus which leads to inhibition of cellular translation through eIF2a phosphorylation, suppressing Mcl-1 biosynthesis. Sindbis virus can regulate 14-3-3 through activation of JNK followed by induction of PKR (for other details see text). AHSV, African horse sickness virus; CHIKV, Chikungunya virus; CCHF, Crimean–Congo haemorrhagic fever virus; DENV, Dengue virus; FasL, Fas (Apo-1/CD95) ligand; JEV, Japanese encephalitis virus; JNK, c-Jun N-terminal kinases; TNF, tumour necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; PKR, (dsRNA)-activated protein kinase; RVFV, Rift valley fever virus; WNV, West Nile virus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4836210&req=5

fig07: Graphic representation of apoptosis and viral replication. Viral infection, in general, can induce both intrinsic and extrinsic apoptotic pathways. Viruses like CHIKV, CCHFV and RVFV initiate extrinsic signals through cell death ligands (e.g. FasL, APO-2L, TRAIL, TNF), causing caspases-8 activation which then triggers caspases-3, -6 and -7). AHSV and WNV directly trigger caspase 3; however, CHIKV targets caspase 9. DENV and WNV affect the intrinsic pathway of apoptosis through stimulation of P53. Once P53 is activated, mitochondria-dependent apoptosis can be activated. Viral infection can also induce PKR and this kinase can affect eIF2a, resulting in activation of effector caspases and initiation of apoptosis. Viruses can also have anti-apoptotic activity. DENV, WNV and JEV trigger survival signalling through PI3K-AKT signalling pathway. PKR can be initiated by Sindbis virus which leads to inhibition of cellular translation through eIF2a phosphorylation, suppressing Mcl-1 biosynthesis. Sindbis virus can regulate 14-3-3 through activation of JNK followed by induction of PKR (for other details see text). AHSV, African horse sickness virus; CHIKV, Chikungunya virus; CCHF, Crimean–Congo haemorrhagic fever virus; DENV, Dengue virus; FasL, Fas (Apo-1/CD95) ligand; JEV, Japanese encephalitis virus; JNK, c-Jun N-terminal kinases; TNF, tumour necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; PKR, (dsRNA)-activated protein kinase; RVFV, Rift valley fever virus; WNV, West Nile virus.
Mentions: To date, several investigations have been carried out on the importance of apoptosis in different virus infections, pathogenesis and replication, but many issues are still unclear and under debate (Refs 212, 213, 214). As summarised in Figure 7, a number of arboviruses such as Sindbis virus, WNV and JEV seem to use apoptosis as a virulence factor to promote their own pathogenesis (215, 216, 217). Each of these viruses has specific targets and biochemical-induced mechanisms during virus-induced programmed cell death. The observations suggest that Sindbis virus-induced apoptosis plays an important role in Sindbis virus pathogenesis and mortality (Ref. 215). After entry of Sindbis virus into the host cell and subsequent formation of Sindbis virus double-stranded RNA intermediates, dsRNA-dependent protein kinase (PKR) recognises these particles (Refs 218, 219, 220). PKR blocks cellular translation through eIF2a phosphorylation, which later can inhibit Mcl-1 (anti-apoptotic Bcl2 family protein) biosynthesis (Ref. 221). PKR also controls c-Jun N-terminal kinases (JNK) through IRS1 phosphorylation and later activates 14-3-3 (Ref. 222). Thus, 14-3-3 affects the accessibility of substrates (e.g., Bad) to kinases and serves to localise kinases to their substrates, thereby leading to release of Bad and disruption of the complex between anti-apoptotic Bcl2 family proteins, Bcl-xl and Bak. Both Bad and Bik can displace Bak from Mcl-1, which results in Bak oligomerization and cytochrome c release, and subsequent induction of apoptosis (Ref. 222). CHIKV triggers the apoptosis machinery and uses apoptotic blebs to evade immune responses and facilitate its dissemination by infecting neighboring cells (Ref. 223). CHIKV infection can induce apoptotic cell death via at least two apoptotic pathways: the intrinsic pathway, which has been reported to be involved in virus replication and results in activation of caspase-9, and the extracellular pathway, which is dependent on the induction of cell surface or soluble death effector ligands that activate caspase-8. Thus, both pathways activate caspase-3 and finally induce cell death, and this facilitates virus release and spread (Ref. 211). The replication of Crimean-Congo haemorrhagic fever virus (CCHFV), an arbovirus from the family Bunyaviridae, is associated with the death receptor pathway of apoptosis. Up-regulation of pro-apoptotic proteins (i.e. BAX and HRK) and novel components of the ER stress-induced apoptotic pathways (i.e. PUMA and Noxa) have also been shown in a CCHFV-infected hepatocyte cell line, which suggests a link between CCHFV replication, ER stress and apoptotic pathways. Notably, differential high levels of transcription factors, such as CHOP, which are activated through ER stress, are present in hepatocytes following CCHFV replication (Ref. 224). In this study, it was shown that the over-expression of IL-8, an apoptosis inhibitor, during CCHFV infection was independent from apoptotic pathways. However, in other studies, a positive correlation was detected between IL-8 induction and DENV infection (Refs 224, 225, 226). In contrast to Sindbis virus, CHIKV and CCHFV replication in infected cells have been proposed to be necessary for apoptosis induction, as demonstrated by the use of UV-inactivated viral particles (Refs 227, 228, 229). The replication of Flaviviruses (e.g. WNV, JEV and DENV) can be limited by virus-induced programmed cell death at the early stage of virus infection. These viruses might block or delay apoptosis via activating several cell survival pathways, such as PI3K/Akt signalling, to improve their replication rate (Refs 227, 230). Blocking PI3K (using LY294002 and wortmannin) showed that the induction of apoptosis might be a result of p38 MAPK activation and did not affect JEV and DENV viral particle production (Ref. 227). In 2001, del Carmen Parquet et al. demonstrated that WNV-induced cytopathic effect was caused during induction of apoptosis and that viral replication is an essential event for virus-induced cell death (Ref. 231). WNV capsid protein has an anti-apoptotic role, ensuring that it can block or delay apoptosis by suppression of the phosphatidylinositol (PI) 3-kinase-dependent process at the early stage of infection (Ref. 230). In addition, Akt is a downstream target of PI3-kinase and can directly phosphorylate the pro-apoptotic protein Bad at position Ser 136 (Ref. 232). WNV can initiate apoptosis through caspases-3 and -12 and p53 after several rounds of replication and it is noteworthy that initial viral dose exerts an influence on kinetics of WNV-induced cell death (Refs 228, 233, 234, 235). After some RNA virus infections, expression of multiple miRNAs in host cells might have either a positive or negative effect on virus replication. One such cellular miRNA, Hs_154, limits WNV replication by inducing apoptosis through inhibition of two anti-apoptotic proteins like CCCTC binding factor (CTCF) and EGFR-co-amplified and overexpressed protein (ECOP) (Refs 227, 236). JEV, an RNA virus, may induce ROS-mediated ASK1-ERK/p38 MAPK activation and thus lead to initiation of apoptosis (Ref. 237). In mouse neuroblastoma cells (line N18) infected with ultraviolet-inactivated JEV (UV-JEV), replication-incompetent JEV virions induced cell death through a ROS-dependent and NF-kB-mediated pathway (Ref. 238). Initial suppression of UV-JEV-induced cell death, followed by co-infection with active or inactive JEV, showed that JEV may trigger cell survival signalling to modify the cell environment for timely virus production (Ref. 238). NS1′ protein, a neuroinvasiveness factor that is only produced by the JEV serogroup of Flaviviruses during their replication, was introduced as a caspase substrate in virus-induced apoptosis; however, use of a caspase inhibitor had no effect on virus replication (Ref. 239). Empirical evidence showed that JEV can affect Bcl-2 expression to increase anti-apoptotic response rather than anti-viral effect to enhance virus persistence and reach equilibrium between replication and cell death (Ref. 240).Figure 7.

Bottom Line: Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern.The arbovirus infection and replication processes are complex, and many factors are involved in their regulation.In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes.

View Article: PubMed Central - PubMed

Affiliation: Zoonotic Diseases and Special Pathogens,National Microbiology Laboratory,Public Health Agency of Canada,1015 Arlington St.,Winnipeg,Manitoba,Canada.

ABSTRACT
Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

No MeSH data available.


Related in: MedlinePlus