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Hinkle JJ, Trychta KA, Wires ES, Osborn RM, Leach JR, Faraz ZF, Svarcbahs R, Richie CT, Dewhurst S, Harvey BK. Subcellular localization of SARS-CoV-2 E and 3a proteins along the secretory pathway. J Mol Histol 2025; 56:98. [PMID: 40025386 PMCID: PMC11872775 DOI: 10.1007/s10735-025-10375-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 02/13/2025] [Indexed: 03/04/2025]
Abstract
SARS-CoV-2 E and 3a proteins are important for the assembly, budding, and release of viral particles. These two transmembrane proteins have been implicated in forming channels in the membrane that allow the transport of ions to favor viral replication. During an active infection, both proteins generally localize to the endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), and the Golgi where viral assembly occurs. The ER and Golgi are critical for the proper packaging and trafficking of cellular proteins along the secretory pathways which determine a protein's final destination inside or outside of the cell. The SARS-CoV-2 virus primarily infects epithelial cells that are highly secretory in nature such as those in the lung and gut. Here we quantified the distribution of SARS-CoV-2 E and 3a proteins along the secretory pathways in a human intestinal epithelial cell line. We used NaturePatternMatch to demonstrate that epitope-tagged E and 3a proteins expressed alone via transient transfection have a similar immunoreactivity pattern as E and 3a proteins expressed by wild-type viral infection. While E and 3a proteins localized with all selected cellular markers to varying degrees, 3a protein displayed a higher correlation coefficient with the Golgi, early/late endosome, lysosome, and plasma membrane when compared to E protein. This work is the first to provide quantification of the subcellular distribution of E and 3a proteins along the multiple components of the secretory pathway and serves as a basis to develop models for examining how E and 3a alter proteostasis within these structures and affect their function.
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Affiliation(s)
- Joshua J Hinkle
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
| | - Kathleen A Trychta
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Emily S Wires
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Raven M Osborn
- School of Medicine & Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Justin R Leach
- School of Medicine & Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Zoha F Faraz
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Reinis Svarcbahs
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Christopher T Richie
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Stephen Dewhurst
- School of Medicine & Dentistry, University of Rochester, Rochester, NY, 14642, USA
| | - Brandon K Harvey
- Intramural Research Program, National Institute on Drug Abuse, NIH, Suite 200, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
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2
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Lee GH, Lee SH, Li XH, Lu QY, Zhan CL, Kim JD, Sim JM, Song HJ, Sun MH, Cui XS. ERK5 is essential for early porcine embryonic development by maintaining Endoplasmic Reticulum homeostasis. Gene 2025; 936:149104. [PMID: 39557370 DOI: 10.1016/j.gene.2024.149104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/13/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024]
Abstract
Extracellular signal-regulated kinase 5 (ERK5), a mitogen-activated protein kinase (MAPK) family member, plays an important role in various biological processes, such as proliferation, apoptosis, differentiation, survival, and cell regulation. However, studies on the effects of ERK5 on porcine preimplantation embryos are limited. In this study, to determine the function of ERK5 during porcine embryo development, ERK5 function was inhibited by adding the ERK5 inhibitor JWG-071. The ERK5 mRNA and protein expression levels tended to decrease from the 4-cell stage compared to the 1-cell and 2-cell stages, suggesting that ERK5 is the maternal gene. During embryonic development in pigs, adding 5 μM of JWG-071 significantly reduced the phosphorylation of ERK5 and the blastocyst development rate (control: 53.44 ± 8.38 %; treatment: 26.65 ± 3.40 %). Additionally, ERK5 inhibition increased the expression of UPR-related proteins, glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP) by inducing ER stress. Compared to the control group, the expression of the autophagy-related proteins LC3 and ATG7 was significantly increased in the ERK5 inhibition group, indicating that the inhibition of ERK5 induced autophagy. In addition, ERK5 inhibition increased the expression of BAX, a pro-apoptotic gene, resulting in apoptosis. In conclusion, the results show that ERK5 inhibition during porcine embryonic development induces autophagy and apoptosis by increasing ER stress, resulting in a negative effect on embryonic development in pigs.
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Affiliation(s)
- Gyu-Hyun Lee
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Song-Hee Lee
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Xiao-Han Li
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Qin-Yue Lu
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Cheng-Lin Zhan
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Ji-Dam Kim
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Jae-Min Sim
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Hyeon-Ji Song
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Ming-Hong Sun
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea; College of Animal Science and Technology, Southwest University, Chongqing 402460, China
| | - Xiang-Shun Cui
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
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Nourazarian A, Yousefi H, Biray Avci C, Shademan B, Behboudi E. The Interplay Between Viral Infection and Cell Death: A Ping-Pong Effect. Adv Virol 2025; 2025:5750575. [PMID: 39959654 PMCID: PMC11824611 DOI: 10.1155/av/5750575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 06/05/2024] [Accepted: 01/10/2025] [Indexed: 02/18/2025] Open
Abstract
Programmed cell death (PCD) is a well-studied cellular mechanism that plays a critical role in immune responses, developmental processes, and the maintenance of tissue homeostasis. However, viruses have developed diverse strategies to bypass or manipulate the host apoptotic machinery to enhance their replication and survival. As a result, the interaction between PCD pathways and viruses has garnered increased interest, leading to many studies being published in recent years. This study aims to provide an overview of the current understanding of PCD pathways and their significance in viral infections. We will discuss various forms of cell death pathways, including apoptosis, autophagy, necroptosis, and pyroptosis, as well as their corresponding molecular mechanisms. In addition, we will show how viruses manipulate host PCD pathways to prevent or delay cell death or facilitate viral replication. This study emphasizes the importance of investigating the mechanisms by which viruses control the host's PCD machinery to gain insight into the evolutionary dynamics of host-pathogen interactions and to develop new approaches for predicting and managing viral threats. Overall, we aimed to highlight new research areas in PCD and viruses, including introduction of new targets for the development of new antiviral drugs to modulate the cellular apoptotic machinery and novel inhibitors of host cell death pathways.
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Affiliation(s)
- Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Hadi Yousefi
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Cigir Biray Avci
- Department of Medical Biology, Faculty of Medicine, EGE University, Izmir, Turkey
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Emad Behboudi
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
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Salvador-Mira M, Sanchez-Cordoba E, Solivella M, Nombela I, Puente-Marin S, Chico V, Perez L, Perez-Berna AJ, Ortega-Villaizan MDM. Endoplasmic reticulum stress triggers unfolded protein response as an antiviral strategy of teleost erythrocytes. Front Immunol 2024; 15:1466870. [PMID: 39660123 PMCID: PMC11628393 DOI: 10.3389/fimmu.2024.1466870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/23/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction Fish nucleated red blood cells (RBCs), also known as erythrocytes, play a crucial role in maintaining immune system balance by modulating protein expression in response to various stimuli, including viral attack. This study explores the intriguing behavior of rainbow trout RBCs when faced with the viral hemorrhagic septicemia virus (VHSV), focusing on the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Methods Rainbow trout RBCs were Ficoll-purified and exposed to ultraviolet (UV)-inactivated VHSV or live VHSV at different multiplicities of infection (MOIs). Using cryo-soft X-ray tomography (cryo-SXT), we uncovered structural and cellular modifications in RBCs exposed to UV-inactivated VHSV. Moreover, RBCs were treated with 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, to investigate its effect on viral replication. Quantitative real-time PCR was also used to analyze the expression of genes related to the UPR and other related cellular pathways. Results and discussion Beyond their antiviral response, RBCs undergo notable intracellular changes to combat the virus. Cryo-SXT highlighted a significant increase in the ER volume. This increase is associated with ER stress and the activation of the UPR pathway. Interestingly, VHSV replication levels augmented in RBCs under ER-stress inhibition by 4-PBA treatment, suggesting that rainbow trout RBCs tune up ER stress to control viral replication. Therefore, our findings suggested the induction of ER stress and subsequent activation UPR signaling in the antiviral response of RBCs to VHSV. The results open a new line of investigation to uncover additional mechanisms that may become novel cellular targets for the development of RBC-targeted antiviral strategies.
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Affiliation(s)
- Maria Salvador-Mira
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Ester Sanchez-Cordoba
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Manuel Solivella
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Ivan Nombela
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Sara Puente-Marin
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Veronica Chico
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | - Luis Perez
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
| | | | - Maria del Mar Ortega-Villaizan
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández (IDiBE-UMH), Elche, Spain
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Shen Z, Qi Y, Yu W, Li S, Liu Z, Li L, Zhu M, Gong C, Hu X. Grass Carp Reovirus (GCRV) infection activates the PERK-eIF2α pathway to promote the viral replication. FISH & SHELLFISH IMMUNOLOGY 2024; 155:110020. [PMID: 39528019 DOI: 10.1016/j.fsi.2024.110020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/16/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Grass carp reovirus (GCRV) belongs to the genus Aquareovirus and is responsible for causing serious hemorrhagic disease in grass carp (Ctenopharyngodon idella), characterized by high mortality rates. Numerous animal viruses have been shown to activate endoplasmic reticulum stress (ERS). However, the potential for GCRV infection to induce ERS and its implications for viral infection remain unclear. In this study, we demonstrated that GCRV infection induces ERS, activates the protein kinase R-like ER kinase (PERK) pathway, and inhibits both the inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) pathways within the unfolded protein response (UPR). Additionally, we modulated the levels of ERS and UPR pathways in CIK cells through drug treatment and small interfering RNAs (siRNAs). Our findings revealed that the onset of ERS accelerated GCRV infection, while the ATF6 and IRE1 pathways within the UPR negatively regulated GCRV infection. Conversely, the PERK pathway facilitated GCRV infection. Furthermore, we showed that GCRV infection induced oxidative stress, with the production of reactive oxygen species (ROS) being positively regulated by the PERK pathway and the downstream gene endoplasmic reticulum oxidoreductase-1α (ERO1α). Notably, ROS promoted GCRV infection. Collectively, our findings indicate that GCRV infection activates ERS, which in turn promotes viral infection through the PERK-ERO1α-ROS signaling pathway. Thus, the PERK pathway may serve as a novel antiviral target for the prevention of GCRV infection.
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Affiliation(s)
- Zeen Shen
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Yanling Qi
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Wenbin Yu
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Song Li
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Zhuo Liu
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Liuyang Li
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Min Zhu
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China
| | - Chengliang Gong
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China; Agricultural Biotechnology Research Institute, Agricultural Biotechnology, and Ecological Research Institute, Soochow University, Suzhou, 215123, China.
| | - Xiaolong Hu
- School of Biology & Basic Medical Science, Soochow University, Suzhou, 215123, China; Agricultural Biotechnology Research Institute, Agricultural Biotechnology, and Ecological Research Institute, Soochow University, Suzhou, 215123, China.
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6
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Shen Z, Li S, Liu Z, Qi Y, Yu W, Zhang X, Zhu M, Hu X, Gong C. GCRV-encoded circRNA circ_20 forms a ternary complex with BIP and PERK to delay virus replication by inhibiting the PERK-eIF2α pathway. Int J Biol Macromol 2024; 281:136314. [PMID: 39370064 DOI: 10.1016/j.ijbiomac.2024.136314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/08/2024]
Abstract
Viral circRNAs play important roles in host-virus interactions. Previous reports showed that grass carp reovirus (GCRV) encodes 32 circRNAs, and circ_20 from the negative strand of GCRV genome segment 7 has the potential to regulate GCRV replication. However, the regulatory mechanism of circ_20 on GCRV remains unknown. In this study, circ_20 was further validated, and circ_20 negatively regulated ERS, the PERK pathway, and ROS production in GCRV-infected cells. Furthermore, circ_20 inhibited the PERK pathway by forming a ternary complex with BIP and PERK, resulting in delaying GCRV replication. RNA pull-down results indicated that the 51-102 nt region of circ_20 interacts with BIP, while the 451-502 and 514-565 nt regions interact with PERK. After the deletion of these interaction regions, the ability of circ_20 to promote BIP-PERK interaction decreases, leading to a decrease in the ability to inhibit GCRV proliferation. These findings uncovered new insights into the complex interplay between viruses and host cells and provided a novel understanding of the significance of viral circRNAs in virus-host interactions.
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Affiliation(s)
- Zeen Shen
- School of Life Sciences, Soochow University, Suzhou 21523, China
| | - Song Li
- School of Life Sciences, Soochow University, Suzhou 21523, China
| | - Zhuo Liu
- School of Life Sciences, Soochow University, Suzhou 21523, China
| | - Yanling Qi
- School of Life Sciences, Soochow University, Suzhou 21523, China
| | - Wenbin Yu
- School of Chemistry and Life Science, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Xing Zhang
- School of Chemistry and Life Science, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Min Zhu
- School of Life Sciences, Soochow University, Suzhou 21523, China
| | - Xiaolong Hu
- School of Life Sciences, Soochow University, Suzhou 21523, China.
| | - Chengliang Gong
- School of Life Sciences, Soochow University, Suzhou 21523, China.
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Kron NS, Fieber LA, Baker L, Campbell C, Schmale MC. Host response to Aplysia Abyssovirus 1 in nervous system and gill. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 159:105211. [PMID: 38885747 PMCID: PMC11378725 DOI: 10.1016/j.dci.2024.105211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/20/2024]
Abstract
The California sea hare (Aplysia californica) is a model for age associated cognitive decline. Recent researched identified a novel nidovirus, Aplysia Abyssovirus 1, with broad tropism enriched in the Aplysia nervous system. This virus is ubiquitous in wild and maricultured, young and old animals without obvious pathology. Here we re-evaluated gene expression data from several previous studies to investigate differential expression in the nervous system and gill in response to virus and aging as well as the mutational spectrum observed in the viral sequences obtained from these datasets. Viral load and age were highly correlated, indicating persistent infection. Upregulated genes in response to virus were enriched for immune genes and signatures of ER and proteostatic stress, while downregulated genes were enriched for mitochondrial metabolism. Differential expression with respect to age suggested increased iron accumulation and decreased glycolysis, fatty acid metabolism, and proteasome function. Interaction of gene expression trends associated with viral infection and aging suggest that viral infection likely plays a role in aging in the Aplysia nervous system. Mutation analysis of viral RNA identified signatures suggesting ADAR and AID/APOBEC like deaminase act as part of Aplysia anti-viral defense.
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Affiliation(s)
- Nicholas S Kron
- Department of Marine Biology and Ecology, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, 4600 Rickenbacker Cswy, Miami, FL, 33149, USA.
| | - Lynne A Fieber
- Department of Marine Biology and Ecology, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, 4600 Rickenbacker Cswy, Miami, FL, 33149, USA
| | - Lydia Baker
- Department of Marine Biology and Ecology, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, 4600 Rickenbacker Cswy, Miami, FL, 33149, USA
| | | | - Michael C Schmale
- Department of Marine Biology and Ecology, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, 4600 Rickenbacker Cswy, Miami, FL, 33149, USA
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Farías MA, Diethelm-Varela B, Kalergis AM, González PA. Interplay between lipid metabolism, lipid droplets and RNA virus replication. Crit Rev Microbiol 2024; 50:515-539. [PMID: 37348003 DOI: 10.1080/1040841x.2023.2224424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 09/20/2022] [Accepted: 01/29/2023] [Indexed: 06/24/2023]
Abstract
Lipids play essential roles in the cell as components of cellular membranes, signaling molecules, and energy storage sources. Lipid droplets are cellular organelles composed of neutral lipids, such as triglycerides and cholesterol esters, and are also considered as cellular energy reserves, yet new functions have been recently associated with these structures, such as regulators of oxidative stress and cellular lipotoxicity, as well as modulators of pathogen infection through immune regulation. Lipid metabolism and lipid droplets participate in the infection process of many RNA viruses and control their replication and assembly, among others. Here, we review and discuss the contribution of lipid metabolism and lipid droplets over the replication cycle of RNA viruses, altogether pointing out potentially new pharmacological antiviral targets associated with lipid metabolism.
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Affiliation(s)
- Mónica A Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo A González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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9
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Gjøen T, Ruyter B, Østbye TK. Effects of eicosapentaneoic acid on innate immune responses in an Atlantic salmon kidney cell line in vitro. PLoS One 2024; 19:e0302286. [PMID: 38805503 PMCID: PMC11132502 DOI: 10.1371/journal.pone.0302286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 04/02/2024] [Indexed: 05/30/2024] Open
Abstract
Studies of the interplay between metabolism and immunity, known as immunometabolism, is steadily transforming immunological research into new understandings of how environmental cues like diet are affecting innate and adaptive immune responses. The aim of this study was to explore antiviral transcriptomic responses under various levels of polyunsaturated fatty acid. Atlantic salmon kidney cells (ASK cell line) were incubated for one week in different levels of the unsaturated n-3 eicosapentaneoic acid (EPA) resulting in cellular levels ranging from 2-20% of total fatty acid. These cells were then stimulated with the viral mimic and interferon inducer poly I:C (30 ug/ml) for 24 hours before total RNA was isolated and sequenced for transcriptomic analyses. Up to 200 uM EPA had no detrimental effects on cell viability and induced very few transcriptional changes in these cells. However, in combination with poly I:C, our results shows that the level of EPA in the cellular membranes exert profound dose dependent effects of the transcriptional profiles induced by this treatment. Metabolic pathways like autophagy, apelin and VEGF signaling were attenuated by EPA whereas transcripts related to fatty acid metabolism, ferroptosis and the PPAR signaling pathways were upregulated. These results suggests that innate antiviral responses are heavily influenced by the fatty acid profile of salmonid cells and constitute another example of the strong linkage between general metabolic pathways and inflammatory responses.
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Affiliation(s)
- Tor Gjøen
- Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosciences, University of Oslo, Oslo, Norway
| | - Bente Ruyter
- Nofima (Norwegian Institute of Food, Fisheries and Aquaculture Research), Ås, Norway
| | - Tone Kari Østbye
- Nofima (Norwegian Institute of Food, Fisheries and Aquaculture Research), Ås, Norway
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10
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Zhang R, Hu Z, Wei D, Li R, Li Y, Zhang Z. Carboplatin restricts peste des petits ruminants virus replication by suppressing the STING-mediated autophagy. Front Vet Sci 2024; 11:1383927. [PMID: 38812563 PMCID: PMC11133560 DOI: 10.3389/fvets.2024.1383927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/30/2024] [Indexed: 05/31/2024] Open
Abstract
Peste des petits ruminants virus (PPRV) is a morbillivirus that causes the acute and highly pathogenic infectious disease peste des petits ruminants (PPR) in small ruminants and poses a major threat to the goat and sheep industries. Currently, there is no effective treatment for PPRV infection. Here, we propose Carboplatin, a platinum-based regimen designed to treat a range of malignancies, as a potential antiviral agent. We showed that Carboplatin exhibits significant antiviral activity against PPRV in a cell culture model. The mechanism of action of Carboplatin against PPRV is mainly attributed to its ability to block STING mediated autophagy. Together, our study supports the discovery of Carboplatin as an antiviral against PPRV and potentially other closely related viruses, sheds light on its mode of action, and establishes STING as a valid and attractive target to counteract viral infection.
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Affiliation(s)
| | | | | | | | - Yanmin Li
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, China
| | - Zhidong Zhang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, China
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11
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Liang YJ, Chiou YW, Chiu APT, Shiao MS, Teng W, Lin CW, Cheng ML, Huang YH, Liang KH, Su CW, Lai CY, Chen CL, Wu JC. Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122. J Med Virol 2023; 95:e29325. [PMID: 38108211 DOI: 10.1002/jmv.29325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 11/27/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.
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Affiliation(s)
- Yuh-Jin Liang
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yu-Wei Chiou
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Abby Pei-Ting Chiu
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, USA
- Department of Biology, University of Washington, Seattle, Washington, USA
| | - Ming-Shi Shiao
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Wei Teng
- Department of Gastroenterology & Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC
| | - Chin-Wei Lin
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Mei-Ling Cheng
- Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
- Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan, ROC
| | - Yen-Hua Huang
- Center for Systems and Synthetic Biology and Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Kung-Hao Liang
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chien-Wei Su
- Department of Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medicine, Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medicine, Division of Holistic and Multidisciplinary Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Internal Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chi-Yu Lai
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chih-Li Chen
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC
| | - Jaw-Ching Wu
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taiwan, ROC
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Dai S, Min YQ, Li Q, Feng K, Jiang Z, Wang Z, Zhang C, Ren F, Fang Y, Zhang J, Zhu Q, Wang M, Wang H, Deng F, Ning YJ. Interactome profiling of Crimean-Congo hemorrhagic fever virus glycoproteins. Nat Commun 2023; 14:7365. [PMID: 37963884 PMCID: PMC10646030 DOI: 10.1038/s41467-023-43206-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 11/02/2023] [Indexed: 11/16/2023] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 pathogen requiring urgent research and development efforts. The glycoproteins of CCHFV, Gn and Gc, are considered to play multiple roles in the viral life cycle by interactions with host cells; however, these interactions remain largely unclear to date. Here, we analyzed the cellular interactomes of CCHFV glycoproteins and identified 45 host proteins as high-confidence Gn/Gc interactors. These host molecules are involved in multiple cellular biological processes potentially associated with the physiological actions of the viral glycoproteins. Then, we elucidated the role of a representative cellular protein, HAX1. HAX1 interacts with Gn by its C-terminus, while its N-terminal region leads to mitochondrial localization. By the strong interaction, HAX1 sequestrates Gn to mitochondria, thus depriving Gn of its normal Golgi localization that is required for functional glycoprotein-mediated progeny virion packaging. Consistently, the inhibitory activity of HAX1 against viral packaging and hence propagation was further elucidated in the contexts of pseudotyped and authentic CCHFV infections in cellular and animal models. Together, the findings provide a systematic CCHFV Gn/Gc-cell protein-protein interaction map, but also unravel a HAX1/mitochondrion-associated host antiviral mechanism, which may facilitate further studies on CCHFV biology and therapeutic approaches.
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Affiliation(s)
- Shiyu Dai
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Suzhou Medical College, Soochow University, Suzhou, 215006, China
| | - Yuan-Qin Min
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Qi Li
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Kuan Feng
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Zhenyu Jiang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Zhiying Wang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Cunhuan Zhang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Fuli Ren
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Yaohui Fang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Jingyuan Zhang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Qiong Zhu
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Manli Wang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Hualin Wang
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Fei Deng
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Yun-Jia Ning
- Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
- State Key Laboratory of Virology and Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
- Hubei Jiangxia Laboratory, Wuhan, 430200, China.
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Chen L, Yang L, Li Y, Liu T, Yang B, Liu L, Wu R. Autophagy and Inflammation: Regulatory Roles in Viral Infections. Biomolecules 2023; 13:1454. [PMID: 37892135 PMCID: PMC10604974 DOI: 10.3390/biom13101454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/19/2023] [Accepted: 09/19/2023] [Indexed: 10/29/2023] Open
Abstract
Autophagy is a highly conserved intracellular degradation pathway in eukaryotic organisms, playing an adaptive role in various pathophysiological processes throughout evolution. Inflammation is the immune system's response to external stimuli and tissue damage. However, persistent inflammatory reactions can lead to a range of inflammatory diseases and cancers. The interaction between autophagy and inflammation is particularly evident during viral infections. As a crucial regulator of inflammation, autophagy can either promote or inhibit the occurrence of inflammatory responses. In turn, inflammation can establish negative feedback loops by modulating autophagy to suppress excessive inflammatory reactions. This interaction is pivotal in the pathogenesis of viral diseases. Therefore, elucidating the regulatory roles of autophagy and inflammation in viral infections will significantly enhance our understanding of the mechanisms underlying related diseases. Furthermore, it will provide new insights and theoretical foundations for disease prevention, treatment, and drug development.
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Affiliation(s)
- Li Chen
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
| | - Limin Yang
- School of Medicine, Dalian University, Dalian 116622, China;
| | - Yingyu Li
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
| | - Tianrun Liu
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
| | - Bolun Yang
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
| | - Lei Liu
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
| | - Rui Wu
- School of Medicine, Jiamusi University, Jiamusi 154007, China; (L.C.); (Y.L.); (T.L.); (B.Y.)
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14
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Li C, Zhang Y, Zhao X, Li L, Kong X. Autophagy regulation of virus infection in aquatic animals. REVIEWS IN AQUACULTURE 2023; 15:1405-1420. [DOI: 10.1111/raq.12785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 01/04/2023] [Indexed: 01/04/2025]
Abstract
AbstractAutophagy is a conserved intracellular degradation process that is required to maintain host homeostasis and cope with invading pathogens. Over the past few decades, studies on mammals have greatly increased our understanding of the relationship between autophagy and virus infection. Autophagy may convey the invader to lysosomes to degrade or activate the host immune response against virus replication. However, many viruses have developed some strategies that evade the degradative nature of autophagy or hijack this pathway for their gain. It follows that autophagy during viral infection is a double‐edged sword. In contrast to mammals, the review on autophagy modulated by the aquatic animal virus is limited. Here, after a brief description of the main information about autophagy, we highlight current progress on the interplays between autophagy and virus infection in aquatic animals, including the phenomenon of autophagy upon virus infection, the effect of modulating autophagy on virus replication, and the crosstalk between autophagy and immune response during virus infection. This review will help us better understand the pathogenic mechanism of aquatic animal viruses and develop proper antiviral countermeasures aimed at modulating autophagy.
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Affiliation(s)
- Chen Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Yunli Zhang
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianliang Zhao
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Li Li
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
| | - Xianghui Kong
- Engineering Lab of Henan Province for Aquatic Animal Disease Control College of Fisheries, Henan Normal University Xinxiang Henan Province PR China
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15
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He L, Li H, Li C, Liu Z, Lu M, Zhang R, Wu D, Wei D, Shao J, Liu M, Wei H, Zhang C, Wang Z, Kong L, Chen Z, Bian H. HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression. Cancer Commun (Lond) 2023; 43:981-1002. [PMID: 37405956 PMCID: PMC10508155 DOI: 10.1002/cac2.12464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 05/06/2023] [Accepted: 06/29/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND The mechanism of hepatitis B virus (HBV)-induced carcinogenesis remains an area of interest. The accumulation of hepatitis B surface antigen in the endoplasmic reticulum (ER) of hepatocytes stimulates persistent ER stress. Activity of the unfolded protein response (UPR) pathway of ER stress may play an important role in inflammatory cancer transformation. How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma (HCC) is still unclear. Here, we aimed to define the key molecule hyaluronan-mediated motility receptor (HMMR) in this process and explore its role under ER stress in HCC development. METHODS An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor progression. Proteomics and transcriptomics analyses were performed to identify the potential key molecule, screen the E3 ligase, and define the activation pathway. Quantitative real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines. Luciferase reporter assay, chromatin immunoprecipitation, coimmunoprecipitation, immunoprecipitation, and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress. Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues. RESULTS We found sustained activation of ER stress in the HBV-transgenic mouse model of hepatitis-fibrosis-HCC. HMMR was transcribed by c/EBP homologous protein (CHOP) and degraded by tripartite motif containing 29 (TRIM29) after ubiquitination under ER stress, which caused the inconsistent expression of mRNA and protein. Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR. HMMR could alleviate ER stress by increasing autophagic lysosome activity. The negative correlation between HMMR and ER stress, positive correlation between HMMR and autophagy, and negative correlation between ER stress and autophagy were verified in human tissues. CONCLUSIONS This study identified the complicated role of HMMR in autophagy and ER stress, that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression, which could be a novel explanation for HBV-related carcinogenesis.
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Affiliation(s)
- Lin He
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Hao Li
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
- Department of Gastroenterologythe General Hospital of Western Theatre CommandChengduSichuanP. R. China
| | - Can Li
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ze‐Kun Liu
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Meng Lu
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ren‐Yu Zhang
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Dong Wu
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ding Wei
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Jie Shao
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Man Liu
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Hao‐Lin Wei
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Cong Zhang
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Zhe Wang
- State Key Laboratory of Cancer BiologyDepartment of PathologyXijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ling‐Min Kong
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Zhi‐Nan Chen
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Huijie Bian
- National Translational Science Centre for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxiP. R. China
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Baďurová L, Polčicová K, Omasta B, Ovečková I, Kocianová E, Tomášková J. 2-Deoxy-D-glucose inhibits lymphocytic choriomeningitis virus propagation by targeting glycoprotein N-glycosylation. Virol J 2023; 20:108. [PMID: 37259080 DOI: 10.1186/s12985-023-02082-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/26/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND Increased glucose uptake and utilization via aerobic glycolysis are among the most prominent hallmarks of tumor cell metabolism. Accumulating evidence suggests that similar metabolic changes are also triggered in many virus-infected cells. Viral propagation, like highly proliferative tumor cells, increases the demand for energy and macromolecular synthesis, leading to high bioenergetic and biosynthetic requirements. Although significant progress has been made in understanding the metabolic changes induced by viruses, the interaction between host cell metabolism and arenavirus infection remains unclear. Our study sheds light on these processes during lymphocytic choriomeningitis virus (LCMV) infection, a model representative of the Arenaviridae family. METHODS The impact of LCMV on glucose metabolism in MRC-5 cells was studied using reverse transcription-quantitative PCR and biochemical assays. A focus-forming assay and western blot analysis were used to determine the effects of glucose deficiency and glycolysis inhibition on the production of infectious LCMV particles. RESULTS Despite changes in the expression of glucose transporters and glycolytic enzymes, LCMV infection did not result in increased glucose uptake or lactate excretion. Accordingly, depriving LCMV-infected cells of extracellular glucose or inhibiting lactate production had no impact on viral propagation. However, treatment with the commonly used glycolytic inhibitor 2-deoxy-D-glucose (2-DG) profoundly reduced the production of infectious LCMV particles. This effect of 2-DG was further shown to be the result of suppressed N-linked glycosylation of the viral glycoprotein. CONCLUSIONS Although our results showed that the LCMV life cycle is not dependent on glucose supply or utilization, they did confirm the importance of N-glycosylation of LCMV GP-C. 2-DG potently reduces LCMV propagation not by disrupting glycolytic flux but by inhibiting N-linked protein glycosylation. These findings highlight the potential for developing new, targeted antiviral therapies that could be relevant to a wider range of arenaviruses.
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Affiliation(s)
- Lucia Baďurová
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Functional Genomics and Proteomics of Plants, Central European Institute of Technology and National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic
| | - Katarína Polčicová
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Božena Omasta
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ingrid Ovečková
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Eva Kocianová
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jana Tomášková
- Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
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MA F, FA C, AJ N, AA S, IA PF, LJ C, PA G. Contribution of carbohydrate-related metabolism in Herpesvirus infections. CURRENT RESEARCH IN MICROBIAL SCIENCES 2023; 4:100192. [PMID: 37273578 PMCID: PMC10238445 DOI: 10.1016/j.crmicr.2023.100192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
Human herpesviruses are enveloped viruses with double-stranded linear DNA genomes highly prevalent in the human population. These viruses are subdivided into three subfamilies, namely alphaherpesvirinae (herpes simplex virus type 1, HSV-1; herpes simplex virus type 2, HSV-2; and varicella-zoster virus, VZV), betaherpesvirinae (human cytomegalovirus, HCMV; human herpesvirus 6, HHV-6; and human herpesvirus 7, HHV-7) and gammaherpesvirinae (Epstein-Barr virus, EBV; and Kaposi's sarcoma-associated herpesvirus, KSHV). Besides encoding numerous molecular determinants to evade the host antiviral responses, these viruses also modulate cellular metabolic processes to promote their replication. Here, we review and discuss existing studies describing an interplay between carbohydrate metabolism and the replication cycle of herpesviruses, altogether highlighting potentially new molecular targets based on these interactions that could be used to block herpesvirus infections.
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Affiliation(s)
- Farías MA
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
| | - Cancino FA
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
| | - Navarro AJ
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
| | - Soto AA
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
| | - Pastén-Ferrada IA
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
| | - Carreño LJ
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - González PA
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile
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Yeh CT, Weng SC, Tsao PN, Shiao SH. The chaperone BiP promotes dengue virus replication and mosquito vitellogenesis in Aedes aegypti. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2023; 155:103930. [PMID: 36921733 DOI: 10.1016/j.ibmb.2023.103930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 05/10/2023]
Abstract
Binding immunoglobulin protein (BiP, also known as GRP78), a chaperone and master regulator of the unfolded protein response (UPR) pathway, plays an essential role in several flavivirus infections, but its functional role in regulating dengue virus replication in the mosquito remains largely unknown. We here demonstrated the interaction between a dengue virus serotype 2 (DENV2) and BiP in Aedes aegypti and report the discovery of a novel functional role of BiP in mosquito vitellogenesis. Silencing Ae. aegypti BiP (AaBiP) expression resulted in the significant inhibition of DENV2 viral genome replication, viral protein production, and infectious viral particle biogenesis. Co-immunoprecipitation assays showed that the DENV2 non-structural protein 1 (NS1) interacts with the AaBiP protein, and silencing AaBiP expression led to enhanced DENV2 NS1 aggregation, indicating that AaBiP plays a role in viral protein stability. A kinetic study focusing on pulse treatment of MG132, a proteasome inhibitor, in AaBiP-silenced mosquitoes showed that DENV2 NS1 was drastically elevated, which further suggests that AaBiP-mediated viral protein degradation is mediated by proteasomal machinery. Silencing of AaBiP also resulted in a reduction in mosquito fertility and fecundity. Depletion of AaBiP inhibited mosquito vitellogenesis due to the reduction of vitellogenin mRNA and elevated aggregation of vitellogenin protein post blood meal, further suppressing ovary development and fecundity. Overall, our results suggest that AaBiP is a dual-function protein with roles in both the regulation of dengue virus replication and mosquito reproduction. Our findings will be useful in the establishment of more efficient strategies for vector-borne disease control.
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Affiliation(s)
- Chun-Ting Yeh
- Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Che Weng
- Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Nien Tsao
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine National Taiwan University, Taipei, Taiwan
| | - Shin-Hong Shiao
- Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Wang S, Yang K, Li C, Liu W, Gao T, Yuan F, Guo R, Liu Z, Tan Y, Hu X, Tian Y, Zhou D. 4-Phenyl-butyric Acid Inhibits Japanese Encephalitis Virus Replication via Inhibiting Endoplasmic Reticulum Stress Response. Viruses 2023; 15:v15020534. [PMID: 36851748 PMCID: PMC9962822 DOI: 10.3390/v15020534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/02/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
Japanese encephalitis virus (JEV) infection causes host endoplasmic reticulum stress (ERS) reaction, and then induces cell apoptosis through the UPR pathway, invading the central nervous system and causing an inflammation storm. The endoplasmic reticulum stress inhibitor, 4-phenyl-butyric acid (4-PBA), has an inhibitory effect on the replication of flavivirus. Here, we studied the effect of 4-PBA on JEV infection both in vitro and vivo. The results showed that 4-PBA treatment could significantly decrease the titer of JEV, inhibit the expression of the JEV NS3 protein (in vitro, p < 0.01) and reduce the positive rate of the JEV E protein (in vivo, p < 0.001). Compared to the control group, 4-PBA treatment can restore the weight of JEV-infected mice, decrease the level of IL-1β in serum and alleviate the abnormalities in brain tissue structure. Endoplasmic reticulum stress test found that the expression level of GRP78 was much lower and activation levels of PERK and IRE1 pathways were reduced in the 4-PBA treatment group. Furthermore, 4-PBA inhibited the UPR pathway activated by NS3, NS4b and NS5 RdRp. The above results indicated that 4-PBA could block JEV replication and inhibit ER stress caused by JEV. Interestingly, 4-PBA could reduce the expression of NS5 by inhibiting transcription (p < 0.001), but had no effect on the expression of NS3 and NS4b. This result may indicate that 4-PBA has antiviral activity independent of the UPR pathway. In summary, the effect of 4-PBA on JEV infection is related to the inhibition of ER stress, and it may be a promising drug for the treatment of Japanese encephalitis.
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20
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Mo Q, Feng K, Dai S, Wu Q, Zhang Z, Ali A, Deng F, Wang H, Ning YJ. Transcriptome profiling highlights regulated biological processes and type III interferon antiviral responses upon Crimean-Congo hemorrhagic fever virus infection. Virol Sin 2023; 38:34-46. [PMID: 36075566 PMCID: PMC10006212 DOI: 10.1016/j.virs.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 (BSL-4) pathogen that causes Crimean-Congo hemorrhagic fever (CCHF) characterized by hemorrhagic manifestation, multiple organ failure and high mortality rate, posing great threat to public health. Despite the recently increasing research efforts on CCHFV, host cell responses associated with CCHFV infection remain to be further characterized. Here, to better understand the cellular response to CCHFV infection, we performed a transcriptomic analysis in human kidney HEK293 cells by high-throughput RNA sequencing (RNA-seq) technology. In total, 496 differentially expressed genes (DEGs), including 361 up-regulated and 135 down-regulated genes, were identified in CCHFV-infected cells. These regulated genes were mainly involved in host processes including defense response to virus, response to stress, regulation of viral process, immune response, metabolism, stimulus, apoptosis and protein catabolic process. Therein, a significant up-regulation of type III interferon (IFN) signaling pathway as well as endoplasmic reticulum (ER) stress response was especially remarkable. Subsequently, representative DEGs from these processes were well validated by RT-qPCR, confirming the RNA-seq results and the typical regulation of IFN responses and ER stress by CCHFV. Furthermore, we demonstrate that not only type I but also type III IFNs (even at low dosages) have substantial anti-CCHFV activities. Collectively, the data may provide new and comprehensive insights into the virus-host interactions and particularly highlights the potential role of type III IFNs in restricting CCHFV, which may help inform further mechanistic delineation of the viral infection and development of anti-CCHFV strategies.
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Affiliation(s)
- Qiong Mo
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Kuan Feng
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Shiyu Dai
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Qiaoli Wu
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Zhong Zhang
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China
| | - Ashaq Ali
- University of Chinese Academy of Sciences, Beijing, 101408, China; Centre of Excellence in Science and Applied Technologies, Islamabad, 45320, Pakistan
| | - Fei Deng
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Hualin Wang
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
| | - Yun-Jia Ning
- State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071/430207, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071/430207, China.
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21
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Yiang GT, Wu CC, Lu CL, Hu WC, Tsai YJ, Huang YM, Su WL, Lu KC. Endoplasmic Reticulum Stress in Elderly Patients with COVID-19: Potential of Melatonin Treatment. Viruses 2023; 15:156. [PMID: 36680196 PMCID: PMC9863214 DOI: 10.3390/v15010156] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/30/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Aging processes, including immunosenescence, inflammation, inflammasome formation, genomic instability, telomeric attrition, and altered autophagy, are involved in viral infections and they may contribute to increased pathophysiological responses to the SARS-CoV-2 infection in the elderly; this poses additional risks of accelerated aging, which could be found even after recovery. Aging is associated with oxidative damage. Moreover, SARS-CoV-2 infections may increase the production of reactive oxygen species and such infections will disturb the Ca++ balance via an endoplasmic reticulum (ER) stress-mediated unfolded protein response. Although vaccine development and anti-inflammation therapy lower the severity of COVID-19, the prevalence and mortality rates are still alarming in some countries worldwide. In this review, we describe the involvement of viral proteins in activating ER stress transducers and their downstream signals and in inducing inflammation and inflammasome formation. Furthermore, we propose the potential of melatonin as an ER stress modulator, owing to its antioxidant, anti-inflammatory, and immunoregulatory effects in viral infections. Considering its strong safety profile, we suggest that additive melatonin supplementation in the elderly could be beneficial in treating COVID-19.
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Affiliation(s)
- Giou-Teng Yiang
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan
- School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Chia-Chao Wu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-Lin Lu
- Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei 24352, Taiwan
| | - Wan-Chung Hu
- Department of Clinical Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan
| | - Yi-Ju Tsai
- Graduate Institute of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei 243, Taiwan
| | - Yiao-Mien Huang
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan
| | - Wen-Lin Su
- School of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei 24352, Taiwan
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan
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22
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Agrawal N, Saini S, Khanna M, Dhawan G, Dhawan U. Pharmacological Manipulation of UPR: Potential Antiviral Strategy Against Chikungunya Virus. Indian J Microbiol 2022; 62:634-640. [PMID: 36458214 PMCID: PMC9705628 DOI: 10.1007/s12088-022-01046-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Abstract Viruses invade the host cells and maneuver the cellular translation machinery to translate the viral proteins in substantial amounts, which may disturb Endoplasmic Reticulum homeostasis leading to induction of Unfolded Protein Response (UPR), a host response pathway involved in viral pathogenesis. Here, we investigated the effect of UPR pathways on the pathogenesis of chikungunya virus infection. We observed that chikungunya virus mediated the modulation of UPR. A positive modulation was observed in the activation of IRE1 and ATF6 branch while the PERK branch of UPR observed suppressed upon virus infection. We further investigated the effect of the inhibition of UPR pathways on chikungunya virus replication using inhibitors for each branch. Cells treated with 3-ethoxy-5,6-dibromosalicylaldehyde (IRE1 inhibitor) and AEBSF (ATF6 inhibitor) significantly inhibits the viral replication process. This study has provided a novel perspective in designing antivirals against chikungunya virus. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12088-022-01046-5.
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Affiliation(s)
- Nishtha Agrawal
- Department of Virology (a Unit of Department of Microbiology), Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, 110007 India
- Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019 India
| | - Sanjesh Saini
- Department of Virology (a Unit of Department of Microbiology), Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, 110007 India
| | - Madhu Khanna
- Department of Virology (a Unit of Department of Microbiology), Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, 110007 India
| | - Gagan Dhawan
- Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019 India
- Delhi School of Skill Enhancement and Entrepreneurship Development, Institution of Eminence, University of Delhi, Delhi, 110007 India
- School of Allied Medical Services, Delhi Skill and Entrepreneurship University, Sector-9, Dwarka, New Delhi, 110077 India
| | - Uma Dhawan
- Department of Biomedical Science, Bhaskaracharya College of Applied Sciences, University of Delhi, Sector-2, Dwarka, New Delhi, 110075 India
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23
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Zhuang H, Hudson E, Han S, Arja RD, Hui W, Lu L, Reeves WH. Microvascular lung injury and endoplasmic reticulum stress in systemic lupus erythematosus-associated alveolar hemorrhage and pulmonary vasculitis. Am J Physiol Lung Cell Mol Physiol 2022; 323:L715-L729. [PMID: 36255715 PMCID: PMC9744657 DOI: 10.1152/ajplung.00051.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 10/13/2022] [Accepted: 10/13/2022] [Indexed: 12/14/2022] Open
Abstract
Human COPA mutations affecting retrograde Golgi-to-endoplasmic reticulum (ER) protein transport cause diffuse alveolar hemorrhage (DAH) and ER stress ("COPA syndrome"). Patients with SLE also can develop DAH. C57BL/6 (B6) mice with pristane-induced lupus develop monocyte-dependent DAH indistinguishable from human DAH, whereas BALB/c mice are resistant. We examined Copa and ER stress in pristane-induced lupus. Copa expression, ER stress, vascular injury, and apoptosis were assessed in mice and COPA was quantified in blood from patients with SLE. Copa mRNA and protein expression were impaired in B6 mice with pristane-induced DAH, but not in pristane-treated BALB/c mice. An ER stress response (increased Hsp5a/BiP, Ddit3/CHOP, Eif2a, and spliced Xbp1) was seen in lungs from pristane-treated B6, but not BALB/c, mice. Resistance of BALB/c mice to DAH was overcome by treating them with low-dose thapsigargin plus pristane. CB6F1 mice did not develop DAH or ER stress, suggesting that susceptibility was recessive. Increased pulmonary expression of von Willebrand factor (Vwf), a marker of endothelial injury, and the chemokine Ccl2 in DAH suggested that pristane promotes lung microvascular injury and monocyte recruitment. Consistent with that possibility, lung endothelial cells and infiltrating bone marrow-derived cells from pristane-treated B6 mice expressed BiP and showed evidence of apoptosis (annexin-V and activated caspase-3 staining). COPA expression also was low in patients with SLE with lung involvement. Pristane-induced DAH may be initiated by endothelial injury, resulting in ER stress, apoptosis of lung endothelial cells, and recruitment of myeloid cells that propagate lung injury. The pathogenesis of DAH in SLE and COPA syndrome may overlap.
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Affiliation(s)
- Haoyang Zhuang
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
| | - Erin Hudson
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
| | - Shuhong Han
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
| | - Rawad Daniel Arja
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
| | - Winnie Hui
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
| | - Li Lu
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida
| | - Westley H Reeves
- Division of Rheumatology, Allergy, & Clinical Immunology, University of Florida, Gainesville, Florida
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida
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24
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Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases. Viruses 2022; 14:v14122686. [PMID: 36560690 PMCID: PMC9781168 DOI: 10.3390/v14122686] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 12/05/2022] Open
Abstract
The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10-15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.
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25
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Shishova A, Dyugay I, Fominykh K, Baryshnikova V, Dereventsova A, Turchenko Y, Slavokhotova AA, Ivin Y, Dmitriev SE, Gmyl A. Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway. Viruses 2022; 14:v14112486. [PMID: 36366584 PMCID: PMC9699254 DOI: 10.3390/v14112486] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 11/12/2022] Open
Abstract
Many viruses are known to trigger endoplasmic reticulum (ER) stress in host cells, which in turn can develop a protective unfolded protein response (UPR). Depending on the conditions, the UPR may lead to either cell survival or programmed cell death. One of three UPR branches involves the upregulation of Xbp1 transcription factor caused by the unconventional cytoplasmic splicing of its mRNA. This process is accomplished by the phosphorylated form of the endoribonuclease/protein kinase Ire1/ERN1. Here, we show that the phosphorylation of Ire1 is up-regulated in HeLa cells early in enterovirus infection but down-regulated at later stages. We also find that Ire1 is cleaved in poliovirus- and coxsackievirus-infected HeLa cells 4-6 h after infection. We further show that the Ire1-mediated Xbp1 mRNA splicing is repressed in infected cells in a time-dependent manner. Thus, our results demonstrate the ability of enteroviruses to actively modulate the Ire1-Xbp1 host defensive pathway by inducing phosphorylation and proteolytic cleavage of the ER stress sensor Ire1, as well as down-regulating its splicing activity. Inactivation of Ire1 could be a novel mode of the UPR manipulation employed by viruses to modify the ER stress response in the infected cells.
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Affiliation(s)
- Anna Shishova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
- Institute for Translational Medicine and Biotechnology, First Moscow State Medical University (Sechenov University), 117418 Moscow, Russia
- Correspondence: (A.S.); (S.E.D.)
| | - Ilya Dyugay
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Ksenia Fominykh
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Victoria Baryshnikova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Alena Dereventsova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Yuriy Turchenko
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Anna A. Slavokhotova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Yury Ivin
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
| | - Sergey E. Dmitriev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
- Correspondence: (A.S.); (S.E.D.)
| | - Anatoly Gmyl
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products RAS (FSBSI “Chumakov FSC R&D IBP RAS”), 108819 Moscow, Russia
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26
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Zhang R, Chen J, Zi R, Ji L, Hu J, Wu Z, Fu Y. Enterovirus 71-induced autophagosome fusion with multivesicular bodies facilitates viral RNA packaging into exosomes. Microb Pathog 2022; 173:105875. [DOI: 10.1016/j.micpath.2022.105875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 10/17/2022] [Accepted: 11/06/2022] [Indexed: 11/09/2022]
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27
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Zhao Y, Li L, Wang X, He S, Shi W, Chen S. Temporal Proteomic and Phosphoproteomic Analysis of EV-A71-Infected Human Cells. J Proteome Res 2022; 21:2367-2384. [DOI: 10.1021/acs.jproteome.2c00237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Yue Zhao
- College of Biological Sciences, China Agricultural University, Beijing 100193, China
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
| | - Lin Li
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
| | - Xinhui Wang
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, Jiangsu, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China
| | - Sudan He
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, Jiangsu, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China
| | - Weifeng Shi
- Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China
| | - She Chen
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
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28
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Metabolic reprogramming and alteration of the redox state in hyper-productive MDCK cells for influenza a virus production. Biologicals 2022; 80:35-42. [PMID: 36114098 DOI: 10.1016/j.biologicals.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Influenza is a global public health issue leading to widespread morbidity and mortality with devastating economic loss annually. Madin-Darby Canine Kidney (MDCK) cell line has been a major cell line for influenza vaccine applications. Though many details of the host metabolic responses upon influenza A virus (IAV) infection have been documented, little is known about the metabolic reprogramming features of a hyper-productive host for IAV vaccine production. In this study, a MDCK cell clone H1 was shown to have a particular high productivity of 30 × 103 virions/cell. The glucose and amino acid metabolism of H1 were evaluated, indicating that the high producer had a particular metabolic reprogramming phenotype compared to its parental cell line (P): elevated glucose uptake, superior tricarboxylic acid cycle flux, moderate amino acid consumption, and better regulation of reactive oxygen species. Combined with the stronger mitochondrial function and mild antiviral and inflammatory responses characterized previously, our results indicated that the high producer had a sufficient intracellular energy supply, and balanced substrate distribution for IAV and host protein synthesis as well as the intracellular redox status. Understanding of these metabolic alterations paves the way for the rational cell line development and reasonable process optimization for high-yield influenza vaccine production.
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29
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Yang M, Wang Y, Yue Y, Liang L, Peng M, Zhao M, Chen Y, Cao X, Li W, Li C, Zhang H, Du J, Zhong R, Xia T, Shu Z. Traditional Chinese medicines as effective agents against influenza virus-induced pneumonia. Biomed Pharmacother 2022; 153:113523. [DOI: 10.1016/j.biopha.2022.113523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/31/2022] [Accepted: 08/08/2022] [Indexed: 11/02/2022] Open
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30
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Farías MA, Diethelm-Varela B, Navarro AJ, Kalergis AM, González PA. Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections. Cells 2022; 11:2224. [PMID: 35883666 PMCID: PMC9324743 DOI: 10.3390/cells11142224] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 12/10/2022] Open
Abstract
Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections.
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Affiliation(s)
- Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Areli J. Navarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
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Zheng L, Liu H, Tian Z, Kay M, Wang H, Wang X, Han H, Xia W, Zhang J, Wang W, Gao Z, Wu Z, Cao H, Geng R, Zhang H. Porcine epidemic diarrhea virus E protein inhibits type I interferon production through endoplasmic reticulum stress response (ERS)-mediated suppression of antiviral proteins translation. Res Vet Sci 2022; 152:236-244. [DOI: 10.1016/j.rvsc.2022.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/22/2022] [Accepted: 07/24/2022] [Indexed: 11/26/2022]
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Jeong GU, Lyu J, Kim KD, Chung YC, Yoon GY, Lee S, Hwang I, Shin WH, Ko J, Lee JY, Kwon YC. SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death. Microbiol Spectr 2022; 10:e0109122. [PMID: 35510852 PMCID: PMC9241873 DOI: 10.1128/spectrum.01091-22] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 04/18/2022] [Indexed: 12/12/2022] Open
Abstract
Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in patients with coronavirus disease 2019 (COVID-19). The most dominant immune cells in the brain are microglia. Yet, the relationship between neurological manifestations, neuroinflammation, and host immune response of microglia to SARS-CoV-2 has not been well characterized. Here, we reported that SARS-CoV-2 can directly infect human microglia, eliciting M1-like proinflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA sequencing (RNA-seq) analysis also revealed that endoplasmic reticulum (ER) stress and immune responses were induced in the early, and apoptotic processes in the late phases of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α), but not the anti-inflammatory cytokine IL-10. After this proinflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of proinflammatory microglial IL-6 and TNF-α and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in patients with COVID-19. IMPORTANCE Recent studies reported neurological and cognitive sequelae in patients with COVID-19 months after the viral infection with several symptoms, including ageusia, anosmia, asthenia, headache, and brain fog. Our conclusions raise awareness of COVID-19-related microglia-mediated neurological disorders to develop treatment strategies for the affected patients. We also indicated that HMC3 was a novel human cell line susceptible to SARS-CoV-2 infection that exhibited cytopathic effects, which could be further used to investigate cellular and molecular mechanisms of neurological manifestations of patients with COVID-19.
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Affiliation(s)
- Gi Uk Jeong
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Jaemyun Lyu
- Arontier Co., Ltd., Seoul, Republic of Korea
| | - Kyun-Do Kim
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Young Cheul Chung
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Gun Young Yoon
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Sumin Lee
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Insu Hwang
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Won-Ho Shin
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Junsu Ko
- Arontier Co., Ltd., Seoul, Republic of Korea
| | - June-Yong Lee
- Department of Microbiology and Immunology, College of Medicine, Yonsei University, Seoul, Republic of Korea
- Institute for Immunology and Immunological Disease, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Chan Kwon
- Center for Convergent Research for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
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Xu P, Tang J, He ZG. Induction of Endoplasmic Reticulum Stress by CdhM Mediates Apoptosis of Macrophage During Mycobacterium tuberculosis Infection. Front Cell Infect Microbiol 2022; 12:877265. [PMID: 35444960 PMCID: PMC9013901 DOI: 10.3389/fcimb.2022.877265] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/08/2022] [Indexed: 11/26/2022] Open
Abstract
The normal operation of the endoplasmic reticulum (ER) is critical for cells and organisms. However, ER stress, caused by imbalanced protein folding, occurs frequently, which perturbs the function of the ER and even results in cell apoptosis eventually. Many insults can induce ER stress; pathogen infection is one of them. Most of the genes involved in ER stress have been reported to be upregulated in Mycobacterium tuberculosis (Mtb) granulomas of humans and mice, implicating that infection with Mtb can induce ER stress. However, little is known about the molecular mechanism of Mtb induction of ER stress. Here, we reveal that Mycobacterium protein CDP-diglyceride hydrolase of Mycobacteriumn (CdhM) could target the ER and cause abnormal ER morphology and cell death. RNA-seq analysis suggests that most of the ER stress-involved genes were modulated by CdhM. Further assessed by biochemical experiments, the transcription and protein levels of ER stress markers BiP and CHOP, as well as the levels of XBP1 splicing and eIF2α phosphorylation, were significantly increased by CdhM, confirming that CdhM could induce ER stress alone or during infection. A single conserved amino acid mutant of CdhM, including L44A, G96A, H150A, and W175A, was incapable of inducing ER stress, which indicates that induction of ER stress by CdhM is specific and functional. Furthermore, CdhM-induced ER stress could also promote apoptosis of macrophages during Mtb infection. Overexpression of CdhM conferred a significant benefit for Mtb replication by releasing Mtb into extracellular during infection of macrophage in vitro, as presented in CFU assays. Overall, our study identified a novel Mtb effector protein CdhM which may promote Mtb dissemination and proliferation by induction of ER stress and apoptosis and provided new insight into the physiological significance of induction of ER stress in tuberculosis (TB) granulomas.
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Affiliation(s)
- Peng Xu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jing Tang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Zheng-Guo He
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Life Science and Technology, Guangxi University, Nanning, China
- *Correspondence: Zheng-Guo He,
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Programmed cell death: the pathways to severe COVID-19? Biochem J 2022; 479:609-628. [PMID: 35244141 PMCID: PMC9022977 DOI: 10.1042/bcj20210602] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023]
Abstract
Two years after the emergence of SARS-CoV-2, our understanding of COVID-19 disease pathogenesis is still incomplete. Despite unprecedented global collaborative scientific efforts and rapid vaccine development, an uneven vaccine roll-out and the emergence of novel variants of concern such as omicron underscore the critical importance of identifying the mechanisms that contribute to this disease. Overt inflammation and cell death have been proposed to be central drivers of severe pathology in COVID-19 patients and their pathways and molecular components therefore present promising targets for host-directed therapeutics. In our review, we summarize the current knowledge on the role and impact of diverse programmed cell death (PCD) pathways on COVID-19 disease. We dissect the complex connection of cell death and inflammatory signaling at the cellular and molecular level and identify a number of critical questions that remain to be addressed. We provide rationale for targeting of cell death as potential COVID-19 treatment and provide an overview of current therapeutics that could potentially enter clinical trials in the near future.
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Wu Y, Zhang Z, Li Y, Li Y. The Regulation of Integrated Stress Response Signaling Pathway on Viral Infection and Viral Antagonism. Front Microbiol 2022; 12:814635. [PMID: 35222313 PMCID: PMC8874136 DOI: 10.3389/fmicb.2021.814635] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 12/15/2021] [Indexed: 12/13/2022] Open
Abstract
The integrated stress response (ISR) is an adaptational signaling pathway induced in response to different stimuli, such as accumulation of unfolded and misfolded proteins, hypoxia, amino acid deprivation, viral infection, and ultraviolet light. It has been known that viral infection can activate the ISR, but the role of the ISR during viral infection is still unclear. In some cases, the ISR is a protective mechanism of host cells against viral infection, while viruses may hijack the ISR for facilitating their replication. This review highlighted recent advances on the induction of the ISR upon viral infection and the downstream responses, such as autophagy, apoptosis, formation of stress granules, and innate immunity response. We then discussed the molecular mechanism of the ISR regulating viral replication and how viruses antagonize this cellular stress response resulting from the ISR.
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Affiliation(s)
- Yongshu Wu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Zhidong Zhang
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yanmin Li
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- *Correspondence: Yanmin Li,
| | - Yijing Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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Wang X, Wei Z, Cheng B, Li J, He Y, Lan T, Kemper T, Lin Y, Jiang B, Jiang Y, Meng Z, Lu M. Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome/multivesicular body axis. Hepatology 2022; 75:438-454. [PMID: 34580902 DOI: 10.1002/hep.32178] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/06/2021] [Accepted: 09/24/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS HBV infection has been reported to trigger endoplasmic reticulum (ER) stress and initiate autophagy. However, how ER stress and autophagy influence HBV production remains elusive. Here, we studied the effect of tunicamycin (TM), an N-glycosylation inhibitor and ER stress inducer, on HBV replication and secretion and examined the underlying mechanisms. APPROACH AND RESULTS Protein disulfide isomerase (an ER marker), microtubule-associated protein 1 light chain 3 beta (an autophagosome [AP] marker), and sequestosome-1 (a typical cargo for autophagic degradation) expression were tested in liver tissues of patients with chronic HBV infection and hepatoma cell lines. The role of TM treatment in HBV production and trafficking was examined in hepatoma cell lines. TM treatment that mimics HBV infection triggered ER stress and increased AP formation, resulting in enhanced HBV replication and secretion of subviral particles (SVPs) and naked capsids. Additionally, TM reduced the number of early endosomes and HBsAg localization in this compartment, causing HBsAg/SVPs to accumulate in the ER. Thus, TM-induced AP formation serves as an alternative pathway for HBsAg/SVP trafficking. Importantly, TM inhibited AP-lysosome fusion, accompanied by enhanced AP/late endosome (LE)/multivesicular body fusion, to release HBsAg/SVPs through, or along with, exosome release. Notably, TM treatment inhibited HBsAg glycosylation, resulting in impairment of HBV virions' envelopment and secretion, but it was not critical for HBsAg/SVP trafficking in our cell systems. CONCLUSIONS TM-induced ER stress and autophagic flux promoted HBV replication and the release of SVPs and naked capsids through the AP-LE/MVB axis.
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Affiliation(s)
- Xueyu Wang
- Department of Infectious DiseasesThe Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina.,Institute of VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
| | - Zhiqiang Wei
- Institute of VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany.,Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina
| | - Bin Cheng
- Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina
| | - Jia Li
- Institute of VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
| | - Yulin He
- Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina
| | - Tingyu Lan
- Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina
| | - Thekla Kemper
- Institute of VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
| | - Yong Lin
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of EducationChongqing Medical UniversityChongqingChina
| | - Bin Jiang
- Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina.,Department of Hepatobiliary Pancreatic SurgeryTaihe HospitalHubei University of MedicineShiyanChina
| | - Yongfang Jiang
- Department of Infectious DiseasesThe Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina
| | - Zhongji Meng
- Institute of Biomedical ResearchHubei Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyanChina.,Department of Infectious DiseasesTaihe HospitalHubei University of MedicineShiyanChina
| | - Mengji Lu
- Institute of VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
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Tavčar Verdev P, Potokar M, Korva M, Resman Rus K, Kolenc M, Avšič Županc T, Zorec R, Jorgačevski J. In human astrocytes neurotropic flaviviruses increase autophagy, yet their replication is autophagy-independent. Cell Mol Life Sci 2022; 79:566. [PMID: 36283999 PMCID: PMC9596533 DOI: 10.1007/s00018-022-04578-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 01/18/2023]
Abstract
Astrocytes, an abundant type of glial cells, are the key cells providing homeostasis in the central nervous system. Due to their susceptibility to infection, combined with high resilience to virus-induced cell death, astrocytes are now considered one of the principal types of cells, responsible for virus retention and dissemination within the brain. Autophagy plays an important role in elimination of intracellular components and in maintaining cellular homeostasis and is also intertwined with the life cycle of viruses. The physiological significance of autophagy in astrocytes, in connection with the life cycle and transmission of viruses, remains poorly investigated. In the present study, we investigated flavivirus-induced modulation of autophagy in human astrocytes by monitoring a tandem fluorescent-tagged LC3 probe (mRFP-EGFP-LC3) with confocal and super-resolution fluorescence microscopy. Astrocytes were infected with tick-borne encephalitis virus (TBEV) or West Nile virus (WNV), both pathogenic flaviviruses, and with mosquito-only flavivirus (MOF), which is considered non-pathogenic. The results revealed that human astrocytes are susceptible to infection with TBEV, WNV and to a much lower extent also to MOF. Infection and replication rates of TBEV and WNV are paralleled by increased rate of autophagy, whereas autophagosome maturation and the size of autophagic compartments are not affected. Modulation of autophagy by rapamycin and wortmannin does not influence TBEV and WNV replication rate, whereas bafilomycin A1 attenuates their replication and infectivity. In human astrocytes infected with MOF, the low infectivity and the lack of efficient replication of this flavivirus are mirrored by the absence of an autophagic response.
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Affiliation(s)
- Petra Tavčar Verdev
- grid.8954.00000 0001 0721 6013Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Maja Potokar
- grid.8954.00000 0001 0721 6013Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia ,grid.433223.7Celica Biomedical, Ljubljana, Slovenia
| | - Miša Korva
- grid.8954.00000 0001 0721 6013Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Katarina Resman Rus
- grid.8954.00000 0001 0721 6013Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Marko Kolenc
- grid.8954.00000 0001 0721 6013Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tatjana Avšič Županc
- grid.8954.00000 0001 0721 6013Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Robert Zorec
- grid.8954.00000 0001 0721 6013Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia ,grid.433223.7Celica Biomedical, Ljubljana, Slovenia
| | - Jernej Jorgačevski
- grid.8954.00000 0001 0721 6013Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia ,grid.433223.7Celica Biomedical, Ljubljana, Slovenia
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Yu S, Gao L, Zhang C, Wang Y, Lan H, Chu Q, Li S, Zheng X. Glycine Ameliorates Endoplasmic Reticulum Stress Induced by Thapsigargin in Porcine Oocytes. Front Cell Dev Biol 2021; 9:733860. [PMID: 34917610 PMCID: PMC8670231 DOI: 10.3389/fcell.2021.733860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/08/2021] [Indexed: 02/05/2023] Open
Abstract
The endoplasmic reticulum (ER) is a multifunctional organelle in the cytoplasm that plays important roles in female mammalian reproduction. The endoplasmic reticulum and mitochondria interact to maintain the normal function of cells by maintaining intracellular calcium homeostasis. As proven by previous research, glycine (Gly) can regulate the intracellular free calcium concentration ([Ca2+]i) and enhance mitochondrial function to improve oocyte maturation in vitro. The effect of Gly on ER function during oocyte in vitro maturation (IVM) is not clear. In this study, we induced an ER stress model with thapsigargin (TG) to explore whether Gly can reverse the ER stress induced by TG treatment and whether it is associated with calcium regulation. The results showed that the addition of Gly could improve the decrease in the average cumulus diameter, the first polar body excretion rate caused by TG-induced ER stress, the cleavage rate and the blastocyst rate. Gly supplementation could reduce the ER stress induced by TG by significantly improving the ER levels and significantly downregulating the expression of genes related to ER stress (Xbp1, ATF4, and ATF6). Moreover, Gly also significantly alleviated the increase in reactive oxygen species (ROS) levels and the decrease in mitochondrial membrane potential (ΔΨ m) to improve mitochondrial function in porcine oocytes exposed to TG. Furthermore, Gly reduced the [Ca2+]i and mitochondrial Ca2+ ([Ca2+]m) levels and restored the ER Ca2+ ([Ca2+]ER) levels in TG-exposed porcine oocytes. Moreover, we found that the increase in [Ca2+]i may be caused by changes in the distribution and expression of inositol 1,4,5-triphosphate receptor (IP3R1) and voltage-dependent anion channel 1 (VDAC1), while Gly can restore the distribution and expression of IP3R1 and VDAC1 to normal levels. Apoptosis-related indexes (Caspase 3 activity and Annexin-V) and gene expression Bax, Cyto C, and Caspase 3) were significantly increased in the TG group, but they could be restored by adding Gly. Our results suggest that Gly can ameliorate ER stress and apoptosis in TG-exposed porcine oocytes and can further enhance the developmental potential of porcine oocytes in vitro.
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Affiliation(s)
- Sicong Yu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Lepeng Gao
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Chang Zhang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yumeng Wang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Hainan Lan
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Qianran Chu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Suo Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Xin Zheng
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
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Bansal S, Limaye AP, Lee J, Fleming T, Poulson C, Omar A, Hachem R, Bharat A, Bremner RM, Smith MA, Mohanakumar T. Circulating exosomes induced by respiratory viral infections in lung transplant recipients activate cellular stress, innate immune pathways and epithelial to mesenchymal transition. Transpl Immunol 2021; 69:101480. [PMID: 34619318 DOI: 10.1016/j.trim.2021.101480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/01/2021] [Accepted: 10/02/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Chronic lung transplant rejection occurs in over 50% of lung transplant recipients and mechanism of chronic rejection is unknown. Evaluation of potential mechanism of exosomes from lung transplant recipients diagnosed with respiratory viral infection (RVI) in inducing chronic lung allograft dysfunction (CLAD). METHOD Exosomes were isolated from lung transplant recipients followed by DNA and RNA isolation from exosomes. Cell signaling mechanisms were studied by co-culturing exosomes with human epithelial cells. Mice were immunized with exosomes and lung homogenates were studied for immune signaling proteins. RESULTS Exosomes from lung transplant recipients with RVI carry nucleic acids which are capable of inducing innate immune signaling, endoplasmic reticulum stress, and epithelial mesenchymal transition. CONCLUSION Therefore, we propose that RVI can lead to induction of exosomes that initiate the process leading to CLAD in mice models. These novel findings identified the molecular mechanisms by which RVI increases the risk of CLAD.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ajit P Limaye
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States of America
| | - John Lee
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Christin Poulson
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ashraf Omar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Ramsey Hachem
- Washington University School of Medicine, Department of Medicine, St. Louis, MO, United States of America
| | - Ankit Bharat
- Northwestern University, Chicago, Chicago, IL, United States of America
| | - Ross M Bremner
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - Michael A Smith
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America
| | - T Mohanakumar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States of America.
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The Crucial Role of NLRP3 Inflammasome in Viral Infection-Associated Fibrosing Interstitial Lung Diseases. Int J Mol Sci 2021; 22:ijms221910447. [PMID: 34638790 PMCID: PMC8509020 DOI: 10.3390/ijms221910447] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/17/2021] [Accepted: 09/24/2021] [Indexed: 12/11/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.
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41
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Wu J, Zhang Z, Teng Z, Abdullah SW, Sun S, Guo H. Sec62 Regulates Endoplasmic Reticulum Stress and Autophagy Balance to Affect Foot-and-Mouth Disease Virus Replication. Front Cell Infect Microbiol 2021; 11:707107. [PMID: 34532300 PMCID: PMC8438241 DOI: 10.3389/fcimb.2021.707107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/10/2021] [Indexed: 01/07/2023] Open
Abstract
Endoplasmic reticulum (ER) stress-induced autophagy is closely associated with viral infection and propagation. However, the intrinsic link between ER stress, autophagy, and viral replication during foot-and-mouth disease virus (FMDV) infection is not fully elucidated. Our previous studies demonstrated that FMDV infection activated the ER stress-associated UPR of the PERK-eIF2a and ATF6 signaling pathway, whereas the IRE1a signaling was suppressed. We found that the activated-ATF6 pathway participated in FMDV-induced autophagy and FMDV replication, while the IRE1α pathway only affected FMDV replication. Further studies indicated that Sec62 was greatly reduced in the later stages of FMDV infection and blocked the activation of the autophagy-related IRE1α-JNK pathway. Moreover, it was also found that Sec62 promoted IRE1a phosphorylation and negatively regulated FMDV proliferation. Importantly, Sec62 may interact with LC3 to regulate ER stress and autophagy balance and eventually contribute to FMDV clearance via fusing with lysosomes. Altogether, these results suggest that Sec62 is a critical molecule in maintaining and recovering ER homeostasis by activating the IRE1α-JNK pathway and delivering autophagosome into the lysosome, thus providing new insights on FMDV-host interactions and novel antiviral therapies.
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Affiliation(s)
- Jin'en Wu
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Zhihui Zhang
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Zhidong Teng
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Sahibzada Waheed Abdullah
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Shiqi Sun
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Huichen Guo
- State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.,College of Animal Science, Yangtze University, Jingzhou, China
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42
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Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
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Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
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43
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Mazel-Sanchez B, Iwaszkiewicz J, Bonifacio JPP, Silva F, Niu C, Strohmeier S, Eletto D, Krammer F, Tan G, Zoete V, Hale BG, Schmolke M. Influenza A viruses balance ER stress with host protein synthesis shutoff. Proc Natl Acad Sci U S A 2021; 118:e2024681118. [PMID: 34479996 PMCID: PMC8433552 DOI: 10.1073/pnas.2024681118] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
Excessive production of viral glycoproteins during infections poses a tremendous stress potential on the endoplasmic reticulum (ER) protein folding machinery of the host cell. The host cell balances this by providing more ER resident chaperones and reducing translation. For viruses, this unfolded protein response (UPR) offers the potential to fold more glycoproteins. We postulated that viruses could have developed means to limit the inevitable ER stress to a beneficial level for viral replication. Using a relevant human pathogen, influenza A virus (IAV), we first established the determinant for ER stress and UPR induction during infection. In contrast to a panel of previous reports, we identified neuraminidase to be the determinant for ER stress induction, and not hemagglutinin. IAV relieves ER stress by expression of its nonstructural protein 1 (NS1). NS1 interferes with the host messenger RNA processing factor CPSF30 and suppresses ER stress response factors, such as XBP1. In vivo viral replication is increased when NS1 antagonizes ER stress induction. Our results reveal how IAV optimizes glycoprotein expression by balancing folding capacity.
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Affiliation(s)
- Beryl Mazel-Sanchez
- Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Justyna Iwaszkiewicz
- Molecular Modelling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Joao P P Bonifacio
- Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Filo Silva
- Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Chengyue Niu
- Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Shirin Strohmeier
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Davide Eletto
- Institute of Medical Virology, University of Zürich, 8057 Zürich, Switzerland
| | - Florian Krammer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Gene Tan
- Infectious Diseases, J. Craig Venter Institute, La Jolla, CA 92037
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Vincent Zoete
- Molecular Modelling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Benjamin G Hale
- Institute of Medical Virology, University of Zürich, 8057 Zürich, Switzerland
| | - Mirco Schmolke
- Department of Microbiology and Molecular Medicine, University of Geneva, 1211 Geneva, Switzerland;
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44
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Oh PS, Kang KW, Ryu SR, Lim S, Sohn MH, Lee SM, Jeong HJ. Evaluation of Photobiogoverning Role of Blue Light Irradiation on Viral Replication. Photochem Photobiol 2021; 98:461-470. [PMID: 34486753 DOI: 10.1111/php.13514] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/01/2021] [Accepted: 09/02/2021] [Indexed: 11/29/2022]
Abstract
Most recently, severe acute respiratory syndrome coronavirus-2 has triggered a global pandemic without successful therapeutics. The goal of the present study was to define the antiviral effect and therapeutic action of blue light irradiation in SARS-CoV-2-infected cells. Vero cells were infected with SARS-CoV-2 (NCCP43326) or mock inoculum at 50 pfu/well. After blue light irradiation, the inhibitory effect was assessed by qPCR and plaque reduction assay. When Vero cells were irradiated to blue light ranging from 1.6 to 10 J cm-2 , SARS-CoV-2 replication was inhibited by up to 80%. The antiviral effect of blue light irradiation was associated with translation suppression via the phosphorylation of eIF2α by prolonging endoplasmic reticulum (ER) stress. The levels of LC3A/B and Beclin-1, which are key markers of autophagy, and the levels of PERK and PDI for ER stress were highly increased, whereas caspase-3 cleavage was inhibited after blue light irradiation in the later stage of infection. Our data revealed that blue light irradiation exerted antiviral and photo-biogoverning activities by prolonging ER stress and stimulating autophagy progression during viral infection. The findings increase our understanding of how photo-energy acts on viral progression and have implications for use in therapeutic strategies against COVID-19.
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Affiliation(s)
- Phil-Sun Oh
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Kyung Won Kang
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea
| | - Seung Rok Ryu
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea
| | - SeokTae Lim
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Myung-Hee Sohn
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Sang-Myeong Lee
- Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan, Korea.,Laboratory of Veterinary Virology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Hwan-Jeong Jeong
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju, Korea
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45
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Movaqar A, Yaghoubi A, Rezaee SAR, Jamehdar SA, Soleimanpour S. Coronaviruses construct an interconnection way with ERAD and autophagy. Future Microbiol 2021; 16:1135-1151. [PMID: 34468179 PMCID: PMC8412035 DOI: 10.2217/fmb-2021-0044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 08/04/2021] [Indexed: 12/20/2022] Open
Abstract
Coronaviruses quickly became a pandemic or epidemic, affecting large numbers of humans, due to their structural features and also because of their impacts on intracellular communications. The knowledge of the intracellular mechanism of virus distribution could help understand the coronavirus's proper effects on different pathways that lead to the infections. They protect themselves from recognition and damage the infected cell by using an enclosed membrane through hijacking the autophagy and endoplasmic reticulum-associated protein degradation pathways. The present study is a comprehensive review of the coronavirus strategy in upregulating the communication network of autophagy and endoplasmic reticulum-associated protein degradation.
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Affiliation(s)
- Aref Movaqar
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atieh Yaghoubi
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - SA Rahim Rezaee
- Inflammation & Inflammatory Diseases Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeid A Jamehdar
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Mashhad University of Medical Science, Mashhad, Iran
- Department of Microbiology & Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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46
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Mudaliar P, Pradeep P, Abraham R, Sreekumar E. Targeting cap-dependent translation to inhibit Chikungunya virus replication: selectivity of p38 MAPK inhibitors to virus-infected cells due to autophagy-mediated down regulation of phospho-ERK. J Gen Virol 2021; 102. [PMID: 34328830 DOI: 10.1099/jgv.0.001629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The 5' capped, message-sense RNA genome of Chikungunya virus (CHIKV) utilizes the host cell machinery for translation. Translation is regulated by eIF2 alpha at the initiation phase and by eIF4F at cap recognition. Translational suppression by eIF2 alpha phosphorylation occurs as an early event in many alphavirus infections. We observe that in CHIKV-infected HEK293 cells, this occurs as a late event, by which time the viral replication has reached an exponential phase, implying its minimal role in virus restriction. The regulation by eIF4F is mediated through the PI3K-Akt-mTOR, p38 MAPK and RAS-RAF-MEK-ERK pathways. A kinetic analysis revealed that CHIKV infection did not modulate AKT phosphorylation, but caused a significant reduction in p38 MAPK phosphorylation. It caused degradation of phospho-ERK 1/2 by increased autophagy, leaving the PI3K-Akt-mTOR and p38 MAPK pathways for pharmacological targeting. mTOR inhibition resulted in moderate reduction in viral titre, but had no effect on CHIKV E2 protein expression, indicating a minimal role of the mTOR complex in virus replication. Inhibition of p38 MAPK using SB202190 caused a significant reduction in viral titre and CHIKV E2 and nsP3 protein expression. Furthermore, inhibiting the two pathways together did not offer any synergism, indicating that inhibiting the p38 MAPK pathway alone is sufficient to cause restriction of CHIKV replication. Meanwhile, in uninfected cells the fully functional RAS-RAF-MEK-ERK pathway can circumvent the effect of p38 MAPK inhibition on cap-dependent translation. Thus, our results show that host-directed antiviral strategies targeting cellular p38 MAPK are worth exploring against Chikungunya as they could be selective against CHIKV-infected cells with minimal effects on uninfected host cells.
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Affiliation(s)
- Prashant Mudaliar
- Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India.,Research Centre, University of Kerala, Thiruvananthapuram 695034, Kerala, India
| | - Parvanendhu Pradeep
- Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India.,Research Centre, University of Kerala, Thiruvananthapuram 695034, Kerala, India
| | - Rachy Abraham
- Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India
| | - Easwaran Sreekumar
- Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India
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47
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Yong SJ. Diseased lungs may hinder COVID-19 development: A possible reason for the low prevalence of COPD in COVID-19 patients. Med Hypotheses 2021; 153:110628. [PMID: 34139599 PMCID: PMC8188770 DOI: 10.1016/j.mehy.2021.110628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 05/28/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022]
Abstract
Presently, it remains unclear why the prevalence of lung diseases, namely chronic obstructive pulmonary disease (COPD), is much lower than other medical comorbidities and the general population among patients with coronavirus disease 2019 (COVID-19). If COVID-19 is a respiratory disease, why is COPD not the leading risk factor for contracting COVID-19? The same odd phenomenon was also observed with other pathogenic human coronaviruses causing severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS), but not other respiratory viral infections such as influenza and respiratory syncytial viruses. One commonly proposed reason for the low COPD rates among COVID-19 patients is the usage of inhaled corticosteroids or bronchodilators that may protect against COVID-19. However, another possible reason not discussed elsewhere is that lungs in a diseased state may not be conducive for the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) to establish COVID-19. For one, COPD causes mucous plugging in large and small airways, which may hinder SARS-CoV-2 from reaching deeper parts of the lungs (i.e., alveoli). Thus, SARS-CoV-2 may only localize to the upper respiratory tract of persons with COPD, causing mild or asymptomatic infections requiring no hospital attention. Even if SARS-CoV-2 reaches the alveoli, cells therein are probably under a heavy burden of endoplasmic reticulum (ER) stress and extensively damaged where it may not support efficient viral replication. As a result, limited SARS-CoV-2 virions would be produced in diseased lungs, preventing the development of COVID-19.
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Affiliation(s)
- Shin Jie Yong
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, Malaysia.
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48
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Kamte YS, Chandwani MN, Michaels AC, O’Donnell LA. Neural Stem Cells: What Happens When They Go Viral? Viruses 2021; 13:v13081468. [PMID: 34452333 PMCID: PMC8402908 DOI: 10.3390/v13081468] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/22/2021] [Accepted: 06/28/2021] [Indexed: 12/25/2022] Open
Abstract
Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.
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49
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Wang H, Xu Y, Sun J, Sui Z. The Novel Curcumin Derivative 1g Induces Mitochondrial and ER-Stress-Dependent Apoptosis in Colon Cancer Cells by Induction of ROS Production. Front Oncol 2021; 11:644197. [PMID: 34195069 PMCID: PMC8236884 DOI: 10.3389/fonc.2021.644197] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/25/2021] [Indexed: 12/24/2022] Open
Abstract
Reactive oxygen species (ROS) play an important role in cellular metabolism. Many chemotherapeutic drugs are known to promote apoptosis through the production of ROS. In the present study, the novel curcumin derivative, 1g, was found to inhibit tumor growth in colon cancer cells both in vitro and in vivo. Bioinformatics was used to analyze the differentially expressed mRNAs. The mechanism of this effect was a change in mitochondrial membrane potential caused by 1g that increased its pro-apoptotic activity. In addition, 1g produced ROS, induced G1 checkpoint blockade, and enhanced endoplasmic reticulum (ER)-stress in colon cancer cells. Conversely, pretreatment with the ROS scavenging agent N-acetyl-l-cysteine (NAC) inhibited the mitochondrial dysfunction caused by 1g and reversed ER-stress, cell cycle stagnation, and apoptosis. Additionally, pretreatment with the p-PERK inhibitor GSK2606414 significantly reduced ER-stress and reversed the apoptosis induced by colon cancer cells. In summary, the production of ROS plays an important role in the destruction of colon cancer cells by 1g and demonstrates that targeted strategies based on ROS represent a promising approach to inhibit colon cancer proliferation. These findings reveal that the novel curcumin derivative 1g represents a potential candidate therapeutics for the treatment of colon cancer cells, via apoptosis caused by mitochondrial dysfunction and endoplasmic reticulum stress.
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Affiliation(s)
- Hao Wang
- Department of Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.,Department of Medicine, Qingdao University, Qingdao, China
| | - Yingxing Xu
- Department of Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.,Department of Medicine, Qingdao University, Qingdao, China
| | - Jialin Sun
- Department of Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.,Department of Medicine, Qingdao University, Qingdao, China
| | - Zhongguo Sui
- Department of Medicine, Affiliated Hospital of Qingdao University, Qingdao, China
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50
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Brimson JM, Prasanth MI, Malar DS, Brimson S, Thitilertdecha P, Tencomnao T. Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy. Expert Opin Ther Targets 2021; 25:435-449. [PMID: 34236922 PMCID: PMC8290373 DOI: 10.1080/14728222.2021.1952987] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
Introduction: Despite the availability of new vaccines for SARS-CoV-2, there has been slow uptake and problems with supply in some parts of the world. Hence, there is still a necessity for drugs that can prevent hospitalization of patients and reduce the strain on health care systems. Drugs with sigma affinity potentially provide protection against the most severe symptoms of SARS-COV-2 and could prevent mortality via interactions with the sigma-1 receptor.Areas covered: This review examines the role of the sigma-1 receptor and autophagy in SARS-CoV-2 infections and how they may be linked. The authors reveal how sigma ligands may reduce the symptoms, complications, and deaths resulting from SARS-CoV-2 and offer insights on those patient cohorts that may benefit most from these drugs.Expert opinion: Drugs with sigma affinity potentially offer protection against the most severe symptoms of SARS-CoV-2 via interactions with the sigma-1 receptor. Agonists of the sigma-1 receptor may provide protection of the mitochondria, activate mitophagy to remove damaged and leaking mitochondria, prevent ER stress, manage calcium ion transport, and induce autophagy to prevent cell death in response to infection.
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Affiliation(s)
- James Michael Brimson
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Mani Iyer Prasanth
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Dicson Sheeja Malar
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Sirikalaya Brimson
- Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Premrutai Thitilertdecha
- Siriraj Research Group in Immunobiology and Therapeutic Sciences, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
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