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1
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Münz C, Campbell GR, Esclatine A, Faure M, Labonte P, Lussignol M, Orvedahl A, Altan-Bonnet N, Bartenschlager R, Beale R, Cirone M, Espert L, Jung J, Leib D, Reggiori F, Sanyal S, Spector SA, Thiel V, Viret C, Wei Y, Wileman T, Wodrich H. Autophagy machinery as exploited by viruses. AUTOPHAGY REPORTS 2025; 4:27694127.2025.2464986. [PMID: 40201908 PMCID: PMC11921968 DOI: 10.1080/27694127.2025.2464986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/17/2025] [Accepted: 01/27/2025] [Indexed: 04/10/2025]
Abstract
Viruses adapt and modulate cellular pathways to allow their replication in host cells. The catabolic pathway of macroautophagy, for simplicity referred to as autophagy, is no exception. In this review, we discuss anti-viral functions of both autophagy and select components of the autophagy machinery, and how viruses have evaded them. Some viruses use the membrane remodeling ability of the autophagy machinery to build their replication compartments in the cytosol or efficiently egress from cells in a non-lytic fashion. Some of the autophagy machinery components and their remodeled membranes can even be found in viral particles as envelopes or single membranes around virus packages that protect them during spreading and transmission. Therefore, studies on autophagy regulation by viral infections can reveal functions of the autophagy machinery beyond lysosomal degradation of cytosolic constituents. Furthermore, they can also pinpoint molecular interactions with which the autophagy machinery can most efficiently be manipulated, and this may be relevant to develop effective disease treatments based on autophagy modulation.
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Affiliation(s)
- Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, ZürichSwitzerland
| | - Grant R Campbell
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of SD, Vermillion, SD, USA
| | - Audrey Esclatine
- Université Paris-Saclay, CEA, CNRS, 10 Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Mathias Faure
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007Lyon, France
| | - Patrick Labonte
- eINRS-Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Marion Lussignol
- Université Paris-Saclay, CEA, CNRS, 10 Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
| | - Anthony Orvedahl
- Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA
| | - Nihal Altan-Bonnet
- Laboratory of Host-Pathogen Dynamics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ralf Bartenschlager
- Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Heidelberg, Germany
- German Cancer Research Center (DKFZ), Division Virus-Associated Carcinogenesis, Heidelberg, Germany
- German Centre for Infection Research, Heidelberg partner site, Heidelberg, Germany
| | - Rupert Beale
- Cell Biology of Infection Laboratory, The Francis Crick Institute, London, UK
- Division of Medicine, University College London, London, UK
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Lucile Espert
- University of Montpellier, Montpellier, France
- CNRS, Institut de Recherche enInfectiologie deMontpellier (IRIM), Montpellier, France
| | - Jae Jung
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - David Leib
- Guarini School of Graduate and Advanced Studies at Dartmouth, Hanover, NH, USA
| | - Fulvio Reggiori
- Department of Biomedicine, Aarhus University, Ole Worms Allé 4, Aarhus C, Denmark
| | - Sumana Sanyal
- Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, UK
- HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Stephen A. Spector
- Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Rady Children’s Hospital, San Diego, CA, USA
| | - Volker Thiel
- Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland; Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Christophe Viret
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007Lyon, France
| | - Yu Wei
- Institut Pasteur-Theravectys Joint Laboratory, Department of Virology, Institut Pasteur, Université Paris Cité, Paris, France
| | - Thomas Wileman
- Norwich Medical School, University of East Anglia
- Quadram Institute Bioscience, Norwich Research Park, Norfolk, UK
| | - Harald Wodrich
- Laboratoire de Microbiologie Fondamentale et Pathogénicité, MFP CNRS UMR, Université de Bordeaux, Bordeaux, France
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Marten AD, Haslitt DP, Martin CA, Karthikeyan A, Swanson DH, Kalera K, Johnson UG, Swarts BM, Conway MJ. Trehalose supports the growth of Aedes aegypti cells and modifies gene expression and dengue virus type 2 replication. PLoS Pathog 2025; 21:e1012795. [PMID: 40327709 PMCID: PMC12077775 DOI: 10.1371/journal.ppat.1012795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 05/14/2025] [Accepted: 04/21/2025] [Indexed: 05/08/2025] Open
Abstract
Trehalose is a non-reducing disaccharide that is the major sugar found in insect hemolymph fluid. Trehalose provides energy, and promotes growth, metamorphosis, stress recovery, chitin synthesis, and insect flight. Trehalase is the only enzyme responsible for the hydrolysis of trehalose, which makes it an attractive molecular target. Here we show that Aedes aegypti (Aag2) cells express trehalase and that they can grow on trehalose-containing cell culture media. Trehalase activity was confirmed by treating Aag2 cells with trehalase inhibitors, which inhibited conversion of trehalose to glucose and reduced cell proliferation. Cell entry of a fluorescent trehalose probe was dependent on trehalose concentration, suggesting that trehalose moves across the cell membrane via passive transport. Culturing Aag2 cells with trehalose-containing cell culture media led to significant changes in gene expression, intracellular lipids, and dengue virus replication and specific infectivity, and increased their susceptibility to trehalase inhibitors. These data describe an in vitro model that can be used to rapidly screen novel trehalase inhibitors and probes and underscores the importance of trehalose metabolism in Ae. aegypti physiology and transmission of a mosquito-borne virus.
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Affiliation(s)
- Andrew D. Marten
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, Michigan, United States of America
| | - Douglas P. Haslitt
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, Michigan, United States of America
| | - Chad A. Martin
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, Michigan, United States of America
| | - Akshitha Karthikeyan
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, Michigan, United States of America
| | - Daniel H. Swanson
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, Michigan, United States of America
| | - Karishma Kalera
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, Michigan, United States of America
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, Michigan, United States of America
| | - Ulysses G. Johnson
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, Michigan, United States of America
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, Michigan, United States of America
| | - Benjamin M. Swarts
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, Michigan, United States of America
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, Michigan, United States of America
| | - Michael J. Conway
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, Michigan, United States of America
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Li F, Deng L, Xu T, Xu L, Xu Z, Lai S, Ai Y, Wang Y, Yan G, Zhu L. Getah virus triggers ROS-mediated autophagy in mouse Leydig cells. Front Microbiol 2025; 15:1519694. [PMID: 39872815 PMCID: PMC11771000 DOI: 10.3389/fmicb.2024.1519694] [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: 10/30/2024] [Accepted: 12/23/2024] [Indexed: 01/30/2025] Open
Abstract
Introduction Getah virus (GETV) is a zoonotic virus transmitted via a mosquito-vertebrate cycle. While previous studies have explored the epidemiology and pathogenicity of GETV in various species, its molecular mechanisms remain largely unexplored. Methods This study investigated the impact of GETV infection and associated molecular mechanisms on reactive oxygen species (ROS) and autophagy levels in mouse Leydig cells both in vivo and in vitro. The male mice and TM3 cells were treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels. Rapamycin (Rapa) and 3-Methyladenine (3- MA) were used to change autophagy in both infected and uninfected TM3 cells. Results and Discussion The findings revealed that GETV infection in mouse testes speciffcally targeted Leydig cells and induced oxidative stress while enhancing autophagy in testicular tissue. Using TM3 cells as an in vitro model, the study confirmed GETV replication in this cell line, triggering increased ROS and autophagy levels. Treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels markedly reduced autophagy in testicular tissue and TM3 cells infected with GETV. Interestingly, the use of rapamycin (Rapa) and 3-Methyladenine (3- MA) led to autophagy change in both infected and uninfected TM3 cells, with no signiffcant alterations in cellular ROS levels. These results indicate that GETV infection elevates ROS levels, subsequently inducing autophagy in mouse Leydig cells. We also found that autophagy plays an important role in GETV replication. When autophagy levels were reduced using NAC and 3-MA, a corresponding decrease in TCID50 was observed. Conversely, upregulation of autophagy using Rapa resulted in an increase in TCID50 of GETV. Therefore, we speculate that GETV may exploit the autophagy pathway to facilitate its replication. These ffndings illuminate the interplay between GETV and host cells, providing valuable insights for therapeutic strategies targeting autophagy in GETV infections.
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Affiliation(s)
- Fengqin Li
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- College of Animal Science, Xichang University, Xichang, China
- Key Laboratory of Animal Disease Detection and Prevention in Panxi District, Xichang University, Xichang, China
| | - Lishuang Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Tong Xu
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Lei Xu
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Siyuan Lai
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yanru Ai
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yanqun Wang
- College of Animal Science, Xichang University, Xichang, China
- Key Laboratory of Animal Disease Detection and Prevention in Panxi District, Xichang University, Xichang, China
| | - Guangwen Yan
- College of Animal Science, Xichang University, Xichang, China
- Key Laboratory of Animal Disease Detection and Prevention in Panxi District, Xichang University, Xichang, China
| | - Ling Zhu
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
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Marten AD, Haslitt DP, Martin CA, Swanson DH, Kalera K, Johnson UG, Swarts BM, Conway MJ. Trehalose supports the growth of Aedes aegypti cells and modifies gene expression and dengue virus replication. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.03.626538. [PMID: 39677712 PMCID: PMC11643125 DOI: 10.1101/2024.12.03.626538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Trehalose is a non-reducing disaccharide that is the major sugar found in insect hemolymph fluid. Trehalose provides energy, and promotes growth, metamorphosis, stress recovery, chitin synthesis, and insect flight. Trehalase is the only enzyme responsible for the hydrolysis of trehalose, which makes it an attractive molecular target. Here we show that Aedes aegypti (Aag2) cells express trehalase and that they can grow on trehalose-containing cell culture media. Trehalase activity was confirmed by treating Aag2 cells with trehalase inhibitors, which inhibited conversion of trehalose to glucose and reduced cell proliferation. Cell entry of a fluorescent trehalose probe was dependent on trehalose concentration, suggesting that trehalose moves across the cell membrane via passive transport. Culturing Aag2 cells with trehalose-containing cell culture media led to significant changes in gene expression, intracellular lipids, and dengue virus replication and specific infectivity, and increased their susceptibility to trehalase inhibitors. These data describe an in vitro model that can be used to rapidly screen novel trehalase inhibitors and probes and underscores the importance of trehalose metabolism in Ae. aegypti physiology and transmission of a mosquito-borne virus.
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Affiliation(s)
- Andrew D Marten
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI 48859, USA
| | - Douglas P Haslitt
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI 48859, USA
| | - Chad A Martin
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI 48859, USA
| | - Daniel H Swanson
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA
| | - Karishma Kalera
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, MI 48859, USA
| | - Ulysses G Johnson
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, MI 48859, USA
| | - Benjamin M Swarts
- Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, USA
- Biochemistry, Cell, and Molecular Biology Graduate Programs, Central Michigan University, Mount Pleasant, MI 48859, USA
| | - Michael J Conway
- Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI 48859, USA
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5
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Song MH, Sun Y, Qiu XB. Hijacking autophagy for infection by flaviviruses. Virus Res 2024; 347:199422. [PMID: 38901564 PMCID: PMC11252935 DOI: 10.1016/j.virusres.2024.199422] [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: 03/10/2024] [Revised: 06/08/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a lysosomal degradative pathway, which regulates the homeostasis of eukaryotic cells. This pathway can degrade misfolded or aggregated proteins, clear damaged organelles, and eliminate intracellular pathogens, including viruses, bacteria, and parasites. But, not all types of viruses are eliminated by autophagy. Flaviviruses (e.g., Yellow fever, Japanese encephalitis, Hepatitis C, Dengue, Zika, and West Nile viruses) are single-stranded and enveloped RNA viruses, and transmitted to humans primarily through the bites of arthropods, leading to severe and widespread illnesses. Like the coronavirus SARS-CoV-II, flaviviruses hijack autophagy for their infection and escape from host immune clearance. Thus, it is possible to control these viral infections by inhibiting autophagy. In this review, we summarize recent research progresses on hijacking of autophagy by flaviviruses and discuss the feasibility of antiviral therapies using autophagy inhibitors.
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Affiliation(s)
- Ming-Hui Song
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yan Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiao-Bo Qiu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 211198, China; Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China.
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6
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Ke PY. Regulation of Autophagosome-Lysosome Fusion by Human Viral Infections. Pathogens 2024; 13:266. [PMID: 38535609 PMCID: PMC10974352 DOI: 10.3390/pathogens13030266] [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: 02/20/2024] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 02/11/2025] Open
Abstract
Autophagy plays a fundamental role in maintaining cellular homeostasis by eliminating intracellular components via lysosomes. Successful degradation through autophagy relies on the fusion of autophagosomes to lysosomes, which leads to the formation of autolysosomes containing acidic proteases that degrade the sequestered materials. Viral infections can exploit autophagy in infected cells to balance virus-host cell interactions by degrading the invading virus or promoting viral growth. In recent years, cumulative studies have indicated that viral infections may interfere with the fusion of autophagosomes and lysosomes, thus benefiting viral replication and associated pathogenesis. In this review, I provide an overview of the current understanding of the molecular mechanism by which human viral infections deregulate autophagosome-lysosome fusion and summarize the physiological significance in the virus life cycle and host cell damage.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; ; Tel.: +886-3-211-8800 (ext. 5115); Fax: +886-3-211-8700
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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7
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Limthongkul J, Akkarasereenon K, Yodweerapong T, Songthammawat P, Tong-Ngam P, Tubsuwan A, Kunkaew N, Kanjanasirirat P, Khumpanied T, Wannalo W, Ubol S, Borwornpinyo S, Ploypradith P, Ponpuak M. Novel Potent Autophagy Inhibitor Ka-003 Inhibits Dengue Virus Replication. Viruses 2023; 15:2012. [PMID: 37896789 PMCID: PMC10611120 DOI: 10.3390/v15102012] [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: 07/22/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Every year, dengue virus (DENV) affects millions of people. Currently, there are no approved drugs for the treatment of DENV infection. Autophagy is a conserved degradation process that was shown to be induced by DENV infection and required for optimal DENV replication. The modulation of autophagy is, therefore, considered an attractive target to treat DENV infection. This study carried out a high-content image screen analysis using Crispr-Cas9 GFP-LC3 knocked-in HeLa cells of a compound library synthesized from or inspired by natural products and their biocongener precursors to discover novel autophagy inhibitors. The screen identified Ka-003 as the most effective compound for decreasing the number of autophagic vacuoles inside cells upon autophagy induction. Ka-003 could inhibit autophagy in a dose-dependent manner at low micromolar concentrations. More importantly, Ka-003 demonstrated the concentration-dependent inhibition of DENV production in Crispr-Cas9 GFP-LC3 knocked-in THP-1 monocytes. The core structure of Ka-003, which is a methyl cyclohexene derivative, resembles those found in mulberry plants, and could be synthetically prepared in a bioinspired fashion. Taken together, data indicate that Ka-003 hampered autophagy and limited DENV replication. The low cytotoxicity of Ka-003 suggests its therapeutic potential, which warrants further studies for the lead optimization of the compound for dengue treatment.
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Affiliation(s)
- Jitra Limthongkul
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand (S.U.)
| | - Kornkamon Akkarasereenon
- Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand (P.P.)
| | - Tanpitcha Yodweerapong
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand (S.U.)
| | - Poramate Songthammawat
- Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand (P.P.)
| | - Pirut Tong-Ngam
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand (A.T.)
| | - Alisa Tubsuwan
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand (A.T.)
| | - Nawapol Kunkaew
- Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Phongthon Kanjanasirirat
- Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Tanawadee Khumpanied
- Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Warawuth Wannalo
- Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Sukathida Ubol
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand (S.U.)
| | - Suparerk Borwornpinyo
- Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Poonsakdi Ploypradith
- Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand (P.P.)
| | - Marisa Ponpuak
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand (S.U.)
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8
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Ke PY. Crosstalk between Autophagy and RLR Signaling. Cells 2023; 12:cells12060956. [PMID: 36980296 PMCID: PMC10047499 DOI: 10.3390/cells12060956] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Autophagy plays a homeostatic role in regulating cellular metabolism by degrading unwanted intracellular materials and acts as a host defense mechanism by eliminating infecting pathogens, such as viruses. Upon viral infection, host cells often activate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling to induce the transcription of type I interferons, thus establishing the first line of the innate antiviral response. In recent years, numerous studies have shown that virus-mediated autophagy activation may benefit viral replication through different actions on host cellular processes, including the modulation of RLR-mediated innate immunity. Here, an overview of the functional molecules and regulatory mechanism of the RLR antiviral immune response as well as autophagy is presented. Moreover, a summary of the current knowledge on the biological role of autophagy in regulating RLR antiviral signaling is provided. The molecular mechanisms underlying the crosstalk between autophagy and RLR innate immunity are also discussed.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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9
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Chaudhary N, Srivastava S, Gupta S, Menon MB, Patel AK. Dengue virus induced autophagy is mediated by HMGB1 and promotes viral propagation. Int J Biol Macromol 2023; 229:624-635. [PMID: 36587643 DOI: 10.1016/j.ijbiomac.2022.12.299] [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: 08/04/2022] [Revised: 12/15/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022]
Abstract
Dengue virus (DENV) exploits various cellular pathways including autophagy to assure enhanced virus propagation. The mechanisms of DENV mediated control of autophagy pathway are largely unknown. Our investigations have revealed a novel role for high-mobility group box1 protein (HMGB1) in regulation of cellular autophagy process in DENV-2 infected A549 cell line. While induction of autophagy by rapamycin treatment resulted in enhanced DENV-2 propagation, the blockade of autophagy flux with bafilomycin A1 suppressed viral replication. Furthermore, siRNA-mediated silencing of HMGB1 significantly abrogated dengue induced autophagy, while LPS induced HMGB1 expression counteracted these effects. Interestingly, silencing of HMGB1 showed reduction of BECN1 and stabilization of BCL-2 protein. On the contrary, LPS induction of HMGB1 resulted in enhanced BECN1 and reduction in BCL-2 levels. This study shows that the modulation of autophagy by DENV-2 is HMGB1/BECN1 dependent. In addition, glycyrrhizic acid (GA), a potent HMGB1 inhibitor suppressed autophagy as well as DENV-2 replication. Altogether, our data suggests that HMGB1 induces BECN1 dependent autophagy to promote DENV-2 replication.
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Affiliation(s)
- Nidhi Chaudhary
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi 110016, India
| | - Shikha Srivastava
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi 110016, India
| | - Sunny Gupta
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi 110016, India
| | - Manoj B Menon
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi 110016, India.
| | - Ashok Kumar Patel
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi 110016, India.
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10
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Ma X, Jia Y, Yuan J, Tang QJ, Gao WC, Zhou GF, Yang RH, Pang W, Zheng CB. Inhibiting cardiac autophagy suppresses Zika virus replication. J Med Virol 2023; 95:e28483. [PMID: 36625392 DOI: 10.1002/jmv.28483] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 12/20/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023]
Abstract
Zika Virus (ZIKV) infection is a global threat. Other than the congenital neurological disorders it causes, ZIKV infection has been reported to induce cardiac complications. However, the precise treatment plans are unclear. Thus, illustrating the pathogenic mechanism of ZIKV in the heart is critical to providing effective prevention and treatment of ZIKV infection. The mechanism of autophagy has been reported recently in Dengue virus infection. Whether or not autophagy participates in ZIKV infection and its role remains unrevealed. This study successfully established the in vitro cardiomyocytes and in vivo mouse models of ZIKV infection to investigate the involvement of autophagy in ZIKV infection. The results showed that ZIKV infection is both time and gradient-dependent. The key autophagy protein, LC3B, increased remarkably after ZIKV infection. Meanwhile, autophagic flux was detected by immunofluorescence. Applying autophagy inhibitors decreased the LC3B levels. Furthermore, the number of viral copies was quantified to evaluate the influence of autophagy during infection. We found that autophagy was actively involved in the ZIKV infection and the inhibition of autophagy could effectively reduce the viral copies, suggesting a potential intervention strategy for reducing ZIKV infection and the undesired complications caused by ZIKV.
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Affiliation(s)
- Xin Ma
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
| | - Yinnong Jia
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
| | - Jing Yuan
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
| | - Qiu-Ju Tang
- Chinese Academy of Sciences, Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Shenzhen, People's Republic of China
| | - Wen-Cong Gao
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
| | - Guang-Feng Zhou
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ren-Hua Yang
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
| | - Wei Pang
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Chang-Bo Zheng
- Yunnan Key Laboratory of Pharmacology for Natural Products, School of Pharmaceutical Science, Kunming Medical University, Kunming, China
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11
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Chen T, Tu S, Ding L, Jin M, Chen H, Zhou H. The role of autophagy in viral infections. J Biomed Sci 2023; 30:5. [PMID: 36653801 PMCID: PMC9846652 DOI: 10.1186/s12929-023-00899-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/10/2023] [Indexed: 01/20/2023] Open
Abstract
Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses and autophagy have armed viruses with multiple strategies to subvert the autophagic machinery and counteract cellular antiviral responses. Specifically, the host cell quickly initiates the autophagy to degrade virus particles or virus components upon a viral infection, while cooperating with anti-viral interferon response to inhibit the virus replication. Degraded virus-derived antigens can be presented to T lymphocytes to orchestrate the adaptive immune response. Nevertheless, some viruses have evolved the ability to inhibit autophagy in order to evade degradation and immune responses. Others induce autophagy, but then hijack autophagosomes as a replication site, or hijack the secretion autophagy pathway to promote maturation and egress of virus particles, thereby increasing replication and transmission efficiency. Interestingly, different viruses have unique strategies to counteract different types of selective autophagy, such as exploiting autophagy to regulate organelle degradation, metabolic processes, and immune responses. In short, this review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions.
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Affiliation(s)
- Tong Chen
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Shaoyu Tu
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Ling Ding
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Meilin Jin
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Huanchun Chen
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Hongbo Zhou
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
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12
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Khan R, Panja S, Ding L, Tang S, Tang W, Kapoor E, Bennett RG, Oupický D. Polymeric Chloroquine as an Effective Antimigration Agent in the Treatment of Pancreatic Cancer. Mol Pharm 2022; 19:4631-4643. [PMID: 36346968 DOI: 10.1021/acs.molpharmaceut.2c00596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hydroxychloroquine (HCQ) has been the subject of multiple recent preclinical and clinical studies for its beneficial use in the combination treatments of different types of cancers. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has been shown to be effective in various cancer models both in vitro and in vivo as an inhibitor of cancer cell migration and experimental lung metastasis. Here, we present detailed in vitro studies that show that low concentrations of PCQ can efficiently inhibit cancer cell migration and colony formation orders of magnitude more effectively compared to HCQ. After intraperitoneal administration of PCQ in vivo, high levels of tumor accumulation and penetration are observed, combined with strong antimetastatic activity in an orthotopic pancreatic cancer model. These studies support the idea that PCQ may be effectively used at low doses as an adjuvant in the therapy of pancreatic cancer. In conjunction with previously published literature, these studies further undergird the potential of PCQ as an anticancer agent.
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Affiliation(s)
- Rubayat Khan
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Sudipta Panja
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Ling Ding
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Siyuan Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Weimin Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Ekta Kapoor
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
| | - Robert G Bennett
- Department of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.,Research Service, Nebraska-Western Iowa Health Care System, Omaha, Nebraska 68105, United States
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
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13
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Vimali J, Yong YK, Murugesan A, Vishnupriya K, Ashwin R, Daniel EA, Balakrishnan P, Raju S, Rosmawati M, Velu V, Larsson M, Shankar EM. Plasma interleukin-7 correlation with human immunodeficiency virus RNA and CD4+ T cell counts, and interleukin-5 with circulating hepatitis B virus DNA may have implications in viral control. Front Med (Lausanne) 2022; 9:1019230. [PMID: 36405584 PMCID: PMC9668853 DOI: 10.3389/fmed.2022.1019230] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/12/2022] [Indexed: 08/30/2023] Open
Abstract
Chronic viral infections represent a leading cause of global morbidity and mortality. Chronic HBV, HCV, and HIV infections result in cytokine perturbations that may hold key implications in understanding the complex disease mechanisms driving virus persistence and/or resolution. Here, we determined the levels of various plasma cytokines using a commercial Bio-Plex Luminex cytokine array in chronic HBV (n = 30), HCV (n = 15), and HIV (n = 40) infections and correlated with corresponding plasma viral loads (PVLs) and liver parameters. We observed differential perturbations in cytokine profiles among the study groups. The cytokines levels positively correlated with PVL and liver transaminases. The monocyte-derived cytokines viz., MIP-1β, IL-8, and TNF-α, and Th2 cytokines like IL-4, IL-5, and IL-13 showed a better correlation with liver enzymes as compared to their corresponding PVLs. Our investigation also identified two cytokines viz., IL-5 and IL-7 that inversely correlated with HBV DNA and HIV PVLs, respectively. Regression analysis adjusted for age showed that every increase of IL-5 by one unit was associated with a reduction in HBV PVL by log10 0.4, whereas, every elevation by a unit of IL-7 was associated with decreased HIV PVL by log10 2.5. We also found that IL-7 levels correlated positively with absolute CD4+ T cell counts in HIV-infected patients. We concluded that plasma IL-5 and IL-7 may likely have a key role on viral control in HBV and HIV infections, respectively. A noteworthy increase in cytokines appears to bear protective and pathological significance, and indeed is reflective of the host's versatile immune armory against viral persistence.
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Affiliation(s)
- Jaisheela Vimali
- Infection Biology, Department of Biotechnology, Central University of Tamil Nadu, Thiruvarur, India
| | - Yean Kong Yong
- Laboratory Centre, Xiamen University Malaysia, Sepang, Selangor, Malaysia
| | - Amudhan Murugesan
- Department of Microbiology, Government Theni Medical College and Hospital, Theni, India
| | | | - Rajeev Ashwin
- Infection Biology, Department of Biotechnology, Central University of Tamil Nadu, Thiruvarur, India
| | - Evangeline Ann Daniel
- National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chennai, India
| | - Pachamuthu Balakrishnan
- Department of Microbiology, Centre for Infectious Diseases, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Sivadoss Raju
- State Public Health Laboratory, Directorate of Public Health and Preventive Medicine, Chennai, India
| | - Mohamed Rosmawati
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Universiti Malaya Medical Center, Kuala Lumpur, Malaysia
| | - Vijayakumar Velu
- Division of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, United States
| | - Marie Larsson
- Division of Molecular Medicine and Virology, Department of Biomedicine and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Esaki M. Shankar
- Infection Biology, Department of Biotechnology, Central University of Tamil Nadu, Thiruvarur, India
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14
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Carter CC, Mast FD, Olivier JP, Bourgeois NM, Kaushansky A, Aitchison JD. Dengue activates mTORC2 signaling to counteract apoptosis and maximize viral replication. Front Cell Infect Microbiol 2022; 12:979996. [PMID: 36171757 PMCID: PMC9510660 DOI: 10.3389/fcimb.2022.979996] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/24/2022] [Indexed: 11/28/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR) functions in two distinct complexes: mTORC1, and mTORC2. mTORC1 has been implicated in the pathogenesis of flaviviruses including dengue, where it contributes to the establishment of a pro-viral autophagic state. Activation of mTORC2 occurs upon infection with some viruses, but its functional role in viral pathogenesis remains poorly understood. In this study, we explore the consequences of a physical protein-protein interaction between dengue non-structural protein 5 (NS5) and host cell mTOR proteins during infection. Using shRNA to differentially target mTORC1 and mTORC2 complexes, we show that mTORC2 is required for optimal dengue replication. Furthermore, we show that mTORC2 is activated during viral replication, and that mTORC2 counteracts virus-induced apoptosis, promoting the survival of infected cells. This work reveals a novel mechanism by which the dengue flavivirus can promote cell survival to maximize viral replication.
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Affiliation(s)
- Christoph C. Carter
- Center for Infectious Disease Research, Seattle, WA, United States
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Fred D. Mast
- Center for Infectious Disease Research, Seattle, WA, United States
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
| | - Jean Paul Olivier
- Center for Infectious Disease Research, Seattle, WA, United States
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
| | - Natasha M. Bourgeois
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
- Department of Global Health, University of Washington, Seattle, WA, United States
| | - Alexis Kaushansky
- Center for Infectious Disease Research, Seattle, WA, United States
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
- Department of Global Health, University of Washington, Seattle, WA, United States
- Department of Pediatrics, University of Washington, Seattle, WA, United States
| | - John D. Aitchison
- Center for Infectious Disease Research, Seattle, WA, United States
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
- Department of Pediatrics, University of Washington, Seattle, WA, United States
- Department of Biochemistry, University of Washington, Seattle, WA, United States
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15
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Lineage Replacement Associated with Fitness Gain in Mammalian Cells and Aedes aegypti: A Catalyst for Dengue Virus Type 2 Transmission. Microorganisms 2022; 10:microorganisms10061100. [PMID: 35744618 PMCID: PMC9231088 DOI: 10.3390/microorganisms10061100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Shifting of virus serotypes and clade replacement events are known to drive dengue epidemics. However, only a few studies have attempted to elucidate the virus attributes that contribute to such epidemics. In 2007, Singapore experienced a dengue outbreak affecting more than 8000 individuals. The outbreak ensued with the shuffling of dominant clades (from clade I to clade II) of Dengue virus 2 (DENV-2) cosmopolitan genotype, at a time when the Aedes premise index was significantly low. Therefore, we hypothesized that clade II had higher epidemic potential and fitness than clade I. To test this hypothesis, we tested the replication and apoptotic qualities of clade I and II isolates in mammalian cells and their ability to infect and disseminate in a field strain of Ae. Aegypti. Our findings indicated that clade II replicated more efficiently in mammalian cells than clade I and possessed higher transmission potential in local vectors. This could collectively improve the epidemic potential of clade II, which dominated during the outbreak in 2007. The findings exemplify complex interactions between the emergence, adaptation and transmission potential of DENV, and testify the epidemiological importance of a deeper understanding of virus and vector dynamics in endemic regions.
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16
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Zhao J, Zhang T, Chen G, Geng N, Guo Z, Cao S, Yang Y, Liu K, Wang S, Zhao Y, Meng F, Liu S, Jiang M, Li N. Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K-AKT-mTOR Signaling Pathways. Front Immunol 2022; 13:746890. [PMID: 35185869 PMCID: PMC8851233 DOI: 10.3389/fimmu.2022.746890] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
Despite autophagy’s pivotal role in the replication of viruses such as duck Tembusu virus (DTMUV), which has caused massive economic losses to the poultry industry in the world, the specific relationships between DTMUV and cellular autophagy remain largely unknown. In response, we investigated the interactions between autophagy and DTMUV, the effects of the structural and non-structural proteins of DTMUV on autophagy, and the autophagy-related signaling pathways induced by DTMUV. Among the results, DTMUV increased the autophagy flux in duck embryo fibroblasts (DEF) and BHK-21 cells, while autophagy facilitated viral replication. After we pharmacologically induced autophagy with rapamycin (RAPA), the replication of DTMUV increased by 15.23-fold compared with the control group of DEF cells. To identify which DTMUV protein primarily induced autophagy, all three structural proteins and seven non-structural proteins of DTMUV were transfected into cells, and the results showed that non-structural protein 3 (NS3) induced significant autophagy in DEF cells. By means of Western blot, immunofluorescence, and transmission electron microscopy, we confirmed that NS3 protein could significantly induce autophagy and autophagy flux. Furthermore, we showed that NS3 induced autophagy in DEF cells through extracellular signal-regulated kinase 2 (ERK2) and phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways using specific inhibitors and RNA interference assays. Finally, autophagy induced by NS3 promoted DTMUV replication. These results provide novel insight into the relationship between DTMUV and autophagy, broadening the current understanding of the molecular pathogenesis of DTMUV.
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Affiliation(s)
- Jun Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Tingting Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China.,Collaborative Innovation Center for the Origin and Control of Emerging Infectious Diseases, College of Basic Medical Sciences, Shandong First Medical University, Taian City, China
| | - Guomin Chen
- Laboratory Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ningwei Geng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Zhiyun Guo
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Shengliang Cao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Yudong Yang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Kuihao Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Siqi Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Yiran Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Fanliang Meng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Sidang Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China
| | - Meijie Jiang
- Laboratory Medicine, Tai'an City Central Hospital, Taian, China
| | - Ning Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, College of Animal Science and Technology, Shandong Agricultural University, Taian City, China.,Sino-German Cooperative Research Centre for Zoonosis of Animal Origin Shandong Province, Shandong Agricultural University, Taian City, China
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17
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Bębnowska D, Niedźwiedzka-Rystwej P. The Interplay between Autophagy and Virus Pathogenesis-The Significance of Autophagy in Viral Hepatitis and Viral Hemorrhagic Fevers. Cells 2022; 11:871. [PMID: 35269494 PMCID: PMC8909602 DOI: 10.3390/cells11050871] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/17/2022] Open
Abstract
Autophagy is a process focused on maintaining the homeostasis of organisms; nevertheless, the role of this process has also been widely documented in viral infections. Thus, xenophagy is a selective form of autophagy targeting viruses. However, the relation between autophagy and viruses is ambiguous-this process may be used as a strategy to fight with a virus, but is also in favor of the virus's replication. In this paper, we have gathered data on autophagy in viral hepatitis and viral hemorrhagic fevers and the relations impacting its viral pathogenesis. Thus, autophagy is a potential therapeutic target, but research is needed to fully understand the mechanisms by which the virus interacts with the autophagic machinery. These studies must be performed in specific research models other than the natural host for many reasons. In this paper, we also indicate Lagovirus europaeus virus as a potentially good research model for acute liver failure and viral hemorrhagic disease.
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Affiliation(s)
- Dominika Bębnowska
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland
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18
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Fader Kaiser CM, Romano PS, Vanrell MC, Pocognoni CA, Jacob J, Caruso B, Delgui LR. Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions. Front Cell Dev Biol 2022; 9:826248. [PMID: 35198567 PMCID: PMC8860030 DOI: 10.3389/fcell.2021.826248] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/22/2021] [Indexed: 12/17/2022] Open
Abstract
Lipid droplets (LD) have long been considered as mere fat drops; however, LD have lately been revealed to be ubiquitous, dynamic and to be present in diverse organelles in which they have a wide range of key functions. Although incompletely understood, the biogenesis of eukaryotic LD initiates with the synthesis of neutral lipids (NL) by enzymes located in the endoplasmic reticulum (ER). The accumulation of NL leads to their segregation into nanometric nuclei which then grow into lenses between the ER leaflets as they are further filled with NL. The lipid composition and interfacial tensions of both ER and the lenses modulate their shape which, together with specific ER proteins, determine the proneness of LD to bud from the ER toward the cytoplasm. The most important function of LD is the buffering of energy. But far beyond this, LD are actively integrated into physiological processes, such as lipid metabolism, control of protein homeostasis, sequestration of toxic lipid metabolic intermediates, protection from stress, and proliferation of tumours. Besides, LD may serve as platforms for pathogen replication and defense. To accomplish these functions, from biogenesis to breakdown, eukaryotic LD have developed mechanisms to travel within the cytoplasm and to establish contact with other organelles. When nutrient deprivation occurs, LD undergo breakdown (lipolysis), which begins with the LD-associated members of the perilipins family PLIN2 and PLIN3 chaperone-mediated autophagy degradation (CMA), a specific type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes. Indeed, PLINs CMA degradation is a prerequisite for further true lipolysis, which occurs via cytosolic lipases or by lysosome luminal lipases when autophagosomes engulf portions of LD and target them to lysosomes. LD play a crucial role in several pathophysiological processes. Increased accumulation of LD in non-adipose cells is commonly observed in numerous infectious diseases caused by intracellular pathogens including viral, bacterial, and parasite infections, and is gradually recognized as a prominent characteristic in a variety of cancers. This review discusses current evidence related to the modulation of LD biogenesis and breakdown caused by intracellular pathogens and cancer.
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Affiliation(s)
- Claudio M Fader Kaiser
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
| | - Patricia S Romano
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
| | - M Cristina Vanrell
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
| | - Cristian A Pocognoni
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
| | - Julieta Jacob
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
| | - Benjamín Caruso
- Instituto de Investigaciones Biologicas y Tecnologicas, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Cordoba, Cordoba, Argentina
| | - Laura R Delgui
- CONICET Dr. Mario H. Burgos Institute of Histology and Embryology (IHEM), Mendoza, Argentina
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19
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Sinha M, Chakraborty U, Kool A, Chakravarti M, Das S, Ghosh S, Thakur L, Khuranna A, Nayak D, Basu B, Kar S, Ray R, Das S. In-vitro antiviral action of Eupatorium perfoliatum against dengue virus infection: Modulation of mTOR signaling and autophagy. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114627. [PMID: 34509603 DOI: 10.1016/j.jep.2021.114627] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/26/2021] [Accepted: 09/08/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dengue virus (DENV) is a re-emerging mosquito-borne flavivirus that has recently engendered large epidemics around the world. Consequently antivirals with effective anti-DENV therapeutic activity are urgently required. In the 18th century, Europeans, as well as native inhabitants of North America, were known to adapt the medicinal property of the common perennial plant Eupatorium perfoliatum L. to treat fever and infections. Previous studies have shown that Eupatorium perfoliatum L. possesses anti-inflammatory, anti-oxidative, anti-plasmodial, anti-bacterial and antiviral activities. However, to the best of our knowledge, no anti-DENV activity of E. perfoliatum L. has been investigated at the molecular level so far. AIM OF STUDY Here, for the first time we have attempted to study the action of E. perfoliatum extract and its few bioactive components i.e., quercetin, caffeic acid and eupafolin against wild primary clinical isolate of DENV-2 infection in an in vitro model. MATERIALS AND METHODS The presence of the bioactive components in the E. perfoliatum extract, were analyzed by HPLC- DAD. Then, CC50 as well as IC50 values of the extract and its bioactive components were measured against DENV in HepG2 cell line. After that, the antiviral activity was studied by Time of addition assay using qRT-PCR. Further, the downstream signalling action of E. perfoliatum extract, was studied by Human phosphorylation MAPK antibody array, followed by immunofluorescence microscopy. Moreover, a molecular docking analysis was done to study the binding affinity of bioactive components of E. perfoliatum extract with TIM-1 transmembrane receptor protein, which is known for viral internalization. RESULT We found that E. perfoliatum extract has marked antiviral activity during pre-treatment against DENV infection in HepG2 cell line. The extract also significantly reduced the DENV induced autophagy in HepG2 cell line as detected by LC3 II localization. The presence of different bioactive compounds in E. perfoliatum extract were confirmed by HPLC-DAD. In the bioactive components, in parallel to earlier studies, quercetin showed the most significant preventive action against DENV infection. Further, in molecular docking analysis also, quercetin showed the strongest binding affinity towards DENV membrane receptor TIM-1 protein. CONCLUSION Our findings suggests that E. perfoliatum extract has significant potential to be an anti-DENV therapeutic agent. Moreover, among the bioactive components, quercetin may have a prophylaxis role in executing the antiviral activity of E. perfoliatum extract against DENV infection.
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Affiliation(s)
- Moonmoon Sinha
- Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata-700019, India; Department of Virology, Dr. Anjali Chatterjee Regional Research Institute, Kolkata-700035, India; Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata-700020, India.
| | - Urmita Chakraborty
- Department of Virology, Dr. Anjali Chatterjee Regional Research Institute, Kolkata-700035, India.
| | - Anirban Kool
- Department of Virology, Dr. Anjali Chatterjee Regional Research Institute, Kolkata-700035, India.
| | - Mousumi Chakravarti
- Department of Virology, Dr. Anjali Chatterjee Regional Research Institute, Kolkata-700035, India.
| | - Souvik Das
- Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Institute, Kolkata-700026, India.
| | - Sandip Ghosh
- Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Institute, Kolkata-700026, India.
| | - Lovnish Thakur
- School of Biosciences, Apeejay Stya University, Gurugram, Haryana-122103, India.
| | - Anil Khuranna
- Central Council for Research in Homoeopathy, Ministry of AYUSH, Govt. of India, Janakpuri, New Delhi-111058, India.
| | - Debadatta Nayak
- Central Council for Research in Homoeopathy, Ministry of AYUSH, Govt. of India, Janakpuri, New Delhi-111058, India.
| | - Biswarup Basu
- Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Institute, Kolkata-700026, India.
| | - Subhabrata Kar
- School of Biosciences, Apeejay Stya University, Gurugram, Haryana-122103, India.
| | - Raja Ray
- Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata-700019, India; Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata-700020, India.
| | - Satadal Das
- Department of Virology, Dr. Anjali Chatterjee Regional Research Institute, Kolkata-700035, India.
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20
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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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21
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van Leur SW, Heunis T, Munnur D, Sanyal S. Pathogenesis and virulence of flavivirus infections. Virulence 2021; 12:2814-2838. [PMID: 34696709 PMCID: PMC8632085 DOI: 10.1080/21505594.2021.1996059] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 10/06/2021] [Accepted: 10/15/2021] [Indexed: 11/01/2022] Open
Abstract
The Flavivirus genus consists of >70 members including several that are considered significant human pathogens. Flaviviruses display a broad spectrum of diseases that can be roughly categorised into two phenotypes - systemic disease involving haemorrhage exemplified by dengue and yellow Fever virus, and neurological complications associated with the likes of West Nile and Zika viruses. Attempts to develop vaccines have been variably successful against some. Besides, mosquito-borne flaviviruses can be vertically transmitted in the arthropods, enabling long term persistence and the possibility of re-emergence. Therefore, developing strategies to combat disease is imperative even if vaccines become available. The cellular interactions of flaviviruses with their human hosts are key to establishing the viral lifecycle on the one hand, and activation of host immunity on the other. The latter should ideally eradicate infection, but often leads to immunopathological and neurological consequences. In this review, we use Dengue and Zika viruses to discuss what we have learned about the cellular and molecular determinants of the viral lifecycle and the accompanying immunopathology, while highlighting current knowledge gaps which need to be addressed in future studies.
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Affiliation(s)
| | - Tiaan Heunis
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
| | - Deeksha Munnur
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
| | - Sumana Sanyal
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
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22
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Yan JM, Zhang WK, Yan LN, Jiao YJ, Zhou CM, Yu XJ. Bunyavirus SFTSV exploits autophagic flux for viral assembly and egress. Autophagy 2021; 18:1599-1612. [PMID: 34747299 PMCID: PMC9298452 DOI: 10.1080/15548627.2021.1994296] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2022] Open
Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging negatively stranded enveloped RNA bunyavirus that causes SFTS with a high case fatality rate of up to 30%. Macroautophagy/autophagy is an evolutionarily conserved process involved in the maintenance of host homeostasis, which exhibits anti-viral or pro-viral responses in reaction to different viral challenges. However, the interaction between the bunyavirus SFTSV and the autophagic process is still largely unclear. By establishing various autophagy-deficient cell lines, we found that SFTSV triggered RB1CC1/FIP200-BECN1-ATG5-dependent classical autophagy flux. SFTSV nucleoprotein induced BECN1-dependent autophagy by disrupting the BECN1-BCL2 association. Importantly, SFTSV utilized autophagy for the viral life cycle, which not only assembled in autophagosomes derived from the ERGIC and Golgi complex, but also utilized autophagic vesicles for exocytosis. Taken together, our results suggest a novel virus-autophagy interaction model in which bunyavirus SFTSV induces classical autophagy flux for viral assembly and egress processes, suggesting that autophagy inhibition may be a novel therapy for treating or releasing SFTS.
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Affiliation(s)
- Jia-Min Yan
- State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China
| | - Wen-Kang Zhang
- State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China
| | - Li-Na Yan
- State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China
| | - Yong-Jun Jiao
- Nhc Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, Nanjing, China
| | - Chuan-Min Zhou
- State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China.,Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xue-Jie Yu
- State Key Laboratory of Virology, School of Public Health, Wuhan University, Wuhan, China
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23
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Wan SW, Lee YR, Ho TS, Chang CP. Regulation of innate immune signaling pathways by autophagy in dengue virus infection. IUBMB Life 2021; 74:170-179. [PMID: 34553486 DOI: 10.1002/iub.2554] [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: 07/12/2021] [Revised: 08/24/2021] [Accepted: 09/07/2021] [Indexed: 11/10/2022]
Abstract
Autophagy is not only an intracellular recycling degradation system that maintains cellular homeostasis but is also a component of innate immunity that contributes to host defense against viral infection. The viral components as well as viral particles trapped in autophagosomes can be delivered to lysosomes for degradation. Abundant evidence indicates that dengue virus (DENV) has evolved the potent ability to hijack or subvert autophagy process for escaping host immunity and promoting viral replication. Moreover, autophagy is often required to deliver viral components to pattern recognition receptors signaling for interferon (IFN)-mediated viral elimination. Hence, this review summarizes DENV-induced autophagy, which exhibits dual effects on proviral activity of promoting replication and antiviral activity to eliminating viral particles.
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Affiliation(s)
- Shu-Wen Wan
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Ying-Ray Lee
- Department of Microbiology and Immunology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzong-Shiann Ho
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.,Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Peng Chang
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.,The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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24
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Teo QW, van Leur SW, Sanyal S. Escaping the Lion's Den: redirecting autophagy for unconventional release and spread of viruses. FEBS J 2021; 288:3913-3927. [PMID: 33044763 DOI: 10.1111/febs.15590] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/01/2020] [Accepted: 10/08/2020] [Indexed: 12/30/2022]
Abstract
Autophagy is an evolutionarily conserved process, designed to maintain cellular homeostasis during a range of internal and external stimuli. Conventionally, autophagy is known for coordinated degradation and recycling of intracellular components and removal of cytosolic pathogens. More recently, several lines of evidence have indicated an unconventional, nondegradative role of autophagy for secretion of cargo that lacks a signal peptide. This process referred to as secretory autophagy has also been implicated in the infection cycle of several virus species. This review focuses on the current evidence available on the nondegradative features of autophagy, emphasizing its potential role and unresolved questions in the release and spread of (-) and (+) RNA viruses.
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Affiliation(s)
- Qi Wen Teo
- HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong
| | - Sophie Wilhelmina van Leur
- HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong.,Sir William Dunn School of Pathology, University of Oxford, UK
| | - Sumana Sanyal
- HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong.,Sir William Dunn School of Pathology, University of Oxford, UK
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25
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Puchkova LV, Kiseleva IV, Polishchuk EV, Broggini M, Ilyechova EY. The Crossroads between Host Copper Metabolism and Influenza Infection. Int J Mol Sci 2021; 22:ijms22115498. [PMID: 34071094 PMCID: PMC8197124 DOI: 10.3390/ijms22115498] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/15/2022] Open
Abstract
Three main approaches are used to combat severe viral respiratory infections. The first is preemptive vaccination that blocks infection. Weakened or dead viral particles, as well as genetic constructs carrying viral proteins or information about them, are used as an antigen. However, the viral genome is very evolutionary labile and changes continuously. Second, chemical agents are used during infection and inhibit the function of a number of viral proteins. However, these drugs lose their effectiveness because the virus can rapidly acquire resistance to them. The third is the search for points in the host metabolism the effect on which would suppress the replication of the virus but would not have a significant effect on the metabolism of the host. Here, we consider the possibility of using the copper metabolic system as a target to reduce the severity of influenza infection. This is facilitated by the fact that, in mammals, copper status can be rapidly reduced by silver nanoparticles and restored after their cancellation.
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Affiliation(s)
- Ludmila V. Puchkova
- International Research Laboratory of Trace Elements Metabolism, ADTS Institute, RC AFMLCS, ITMO University, 197101 St. Petersburg, Russia;
| | - Irina V. Kiseleva
- Department of Virology, Institute of Experimental Medicine, 197376 St. Petersburg, Russia;
| | | | - Massimo Broggini
- Istituto di Ricerche Farmacologiche “Mario Negri”, IRCCS, 20156 Milan, Italy;
| | - Ekaterina Yu. Ilyechova
- International Research Laboratory of Trace Elements Metabolism, ADTS Institute, RC AFMLCS, ITMO University, 197101 St. Petersburg, Russia;
- Department of Molecular Genetics, Institute of Experimental Medicine, 197376 St. Petersburg, Russia
- Correspondence: ; Tel.: +7-921-760-5274
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26
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Wu K, Fan S, Zou L, Zhao F, Ma S, Fan J, Li X, Zhao M, Yan H, Chen J. Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection. Front Microbiol 2021; 12:651952. [PMID: 34093468 PMCID: PMC8175637 DOI: 10.3389/fmicb.2021.651952] [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: 01/11/2021] [Accepted: 04/21/2021] [Indexed: 12/17/2022] Open
Abstract
Diseases caused by Flaviviridae have a wide global and economic impact due to high morbidity and mortality. Flaviviridae infection usually leads to severe, acute or chronic diseases, such as liver injury and liver cancer resulting from hepatitis C virus (HCV) infection, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) caused by dengue virus (DENV). Given the highly complex pathogenesis of Flaviviridae infections, they are still not fully understood at present. Accumulating evidence suggests that host autophagy is disrupted to regulate the life cycle of Flaviviridae. Organelle-specific autophagy is able to selectively target different organelles for quality control, which is essential for regulating cellular homeostasis. As an important sub process of autophagy, lipophagy regulates lipid metabolism by targeting lipid droplets (LDs) and is also closely related to the infection of a variety of pathogenic microorganisms. In this review, we briefly understand the LDs interaction relationship with Flaviviridae infection, outline the molecular events of how lipophagy occurs and the related research progress on the regulatory mechanisms of lipophagy in Flaviviridae infection. Exploring the crosstalk between viral infection and lipophagy induced molecular events may provide new avenues for antiviral therapy.
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Affiliation(s)
- Keke Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Shuangqi Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Linke Zou
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Feifan Zhao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Shengming Ma
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Jindai Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Xiaowen Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Mingqiu Zhao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Huichao Yan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Jinding Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
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27
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Xu Q, Huang L, Xing J, Zhang J, Li H, Liu L, Hu C, Liao M, Yue J, Qi W. Japanese encephalitis virus manipulates lysosomes membrane for RNA replication and utilizes autophagy components for intracellular growth. Vet Microbiol 2021; 255:109025. [PMID: 33725516 DOI: 10.1016/j.vetmic.2021.109025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
Japanese encephalitis virus is absolutely dependent on their host cells and has evolved various strategies to manipulate the cellular secretory pathways for viral replication. However, how cellular secretory pathways are hijacked, and the origin of the viral vesicles remains elusive during JEV replication. Here we show how JEV manipulates multiple components of the cellular secretory pathway, including autophagic machinery, to generate a superior environment for genome replication. We utilized double-strand RNA antibodies to label JEV RNA complex seeking the viral replication compartments and found that JEV genome replication takes place in lysosomes (LAMP1), not in autophagosomes (LC3). Subsequently, in situ hybridization results showed that viral RNAs (vRNAs) of JEV strongly colocalized with LAMP1. What surprised us was that JEV vRNAs markedly colocalized with LC3, indicating that autophagy plays an active role in JEV replication. Interestingly, we found that JEV utilized autophagic components for intracellular growth in an autophagy-dependent manner and the fusion of autophagosome-lysosome plays a positive role in JEV post-RNA replication processes. Collectively, our findings demonstrate that JEV can manipulate cellular secretory pathway to form genome replication organelles and exploit autophagy components for intracellular growth, providing new insights into the life cycle of JEV and uncovering an attractive target for antiviral drugs.
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Affiliation(s)
- Qiang Xu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Lihong Huang
- Department of Biomedical Sciences, City University of Hong Kong, 999077, Hong Kong, China
| | - Jinchao Xing
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Jiahao Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Huanan Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Lele Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China
| | - Chen Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Ming Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China
| | - Jianbo Yue
- Department of Biomedical Sciences, City University of Hong Kong, 999077, Hong Kong, China.
| | - Wenbao Qi
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, 510642, China.
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28
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Li M, Xing D, Su D, Wang D, Gao H, Lan C, Gu Z, Zhao T, Li C. Transcriptome Analysis of Responses to Dengue Virus 2 Infection in Aedes albopictus (Skuse) C6/36 Cells. Viruses 2021; 13:v13020343. [PMID: 33671824 PMCID: PMC7926344 DOI: 10.3390/v13020343] [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: 01/14/2021] [Revised: 02/15/2021] [Accepted: 02/19/2021] [Indexed: 12/31/2022] Open
Abstract
Dengue virus (DENV), a member of the Flavivirus genus of the Flaviviridae family, can cause dengue fever (DF) and more serious diseases and thus imposes a heavy burden worldwide. As the main vector of DENV, mosquitoes are a serious hazard. After infection, they induce a complex host–pathogen interaction mechanism. Our goal is to further study the interaction mechanism of viruses in homologous, sensitive, and repeatable C6/36 cell vectors. Transcriptome sequencing (RNA-Seq) technology was applied to the host transcript profiles of C6/36 cells infected with DENV2. Then, bioinformatics analysis was used to identify significant differentially expressed genes and the associated biological processes. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to verify the sequencing data. A total of 1239 DEGs were found by transcriptional analysis of Aedes albopictus C6/36 cells that were infected and uninfected with dengue virus, among which 1133 were upregulated and 106 were downregulated. Further bioinformatics analysis showed that the upregulated DEGs were significantly enriched in signaling pathways such as the MAPK, Hippo, FoxO, Wnt, mTOR, and Notch; metabolic pathways and cellular physiological processes such as autophagy, endocytosis, and apoptosis. Downregulated DEGs were mainly enriched in DNA replication, pyrimidine metabolism, and repair pathways, including BER, NER, and MMR. The qRT-PCR results showed that the concordance between the RNA-Seq and RT-qPCR data was very high (92.3%). The results of this study provide more information about DENV2 infection of C6/36 cells at the transcriptome level, laying a foundation for further research on mosquito vector–virus interactions. These data provide candidate antiviral genes that can be used for further functional verification in the future.
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29
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Wang Y, Qiao J, Zhang D, Zhong C, Wang S, Li X, Feng L, Shi S, Wang B, Liu Q. Systematic identification of autophagy-related proteins in Aedes albopictus. PLoS One 2021; 16:e0245694. [PMID: 33465164 PMCID: PMC7815101 DOI: 10.1371/journal.pone.0245694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/05/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is a conserved cellular process playing a role in maintenance of cellular homeostasis and response to changing nutrient conditions via degradation and recirculation of cellular redundant components. Autophagy-related proteins (Atg) play important function in autophagy pathway. Aedes albopictus mosquito is an effective vector transmitting multiple viruses which cause serious human diseases. Moreover, Aedes albopictus mosquito is becoming a serious threat to human health due to its widening distribution in recent years and thus worth of more research attention. It was reported that autophagy might play a role in viral infection in Aedes mosquito. To better understand the interaction between autophagy and arbovirus infection in mosquito system, it is necessary to identify autophagy pathway in the system. However, autophagy in Aedes albopictus mosquito is still poorly understood so far. We recently identified AaAtg8, the first Atg protein reported in Aedes albopictus mosquito. This work further identified twelve atg genes in Aedes albopictus mosquito. Sequence and phylogenetic analysis of the twelve atg genes were performed. Expression profiles of all the twelve Aaatg genes in different developmental stages and genders of Aedes albopictus mosquito were conducted. Effects of chemicals inhibiting or inducing autophagy on the levels of eight identified AaAtg proteins were examined. The function of two identified AaAtg proteins AaAtg6 and AaAtg16 and their response to arbovirus SINV infection were studied preliminarily. Taken together, this work systematically identified Aedes albopictus atg genes and provided basic information which might help to elucidate the autophagy pathway and the role of autophagy in arbovirus infection in Aedes mosquito system.
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Affiliation(s)
- Yu Wang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Jialu Qiao
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Dandan Zhang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Chunyan Zhong
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Shengya Wang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Xiaomei Li
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Lingyan Feng
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Shen Shi
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Bingxue Wang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
| | - Qingzhen Liu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
- * E-mail:
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Mészáros B, Sámano-Sánchez H, Alvarado-Valverde J, Čalyševa J, Martínez-Pérez E, Alves R, Shields DC, Kumar M, Rippmann F, Chemes LB, Gibson TJ. Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications. Sci Signal 2021; 14:eabd0334. [PMID: 33436497 PMCID: PMC7928535 DOI: 10.1126/scisignal.abd0334] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022]
Abstract
The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.
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Affiliation(s)
- Bálint Mészáros
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
| | - Hugo Sámano-Sánchez
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Jesús Alvarado-Valverde
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences
| | - Jelena Čalyševa
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences
| | - Elizabeth Martínez-Pérez
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
- Laboratorio de bioinformática estructural, Fundación Instituto Leloir, C1405BWE Buenos Aires, Argentina
| | - Renato Alves
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Denis C Shields
- School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Manjeet Kumar
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
| | - Friedrich Rippmann
- Computational Chemistry & Biology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
| | - Lucía B Chemes
- Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo A. Ugalde", IIB-UNSAM, IIBIO-CONICET, Universidad Nacional de San Martín, CP1650 San Martín, Buenos Aires, Argentina.
| | - Toby J Gibson
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
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Scroggs SLP, Gass JT, Chinnasamy R, Widen SG, Azar SR, Rossi SL, Arterburn JB, Vasilakis N, Hanley KA. Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness. Virology 2021; 552:94-106. [PMID: 33120225 PMCID: PMC7528753 DOI: 10.1016/j.virol.2020.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/30/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023]
Abstract
Drugs against flaviviruses such as dengue (DENV) and Zika (ZIKV) virus are urgently needed. We previously demonstrated that three fluoroquinolones, ciprofloxacin, enoxacin, and difloxacin, suppress replication of six flaviviruses. To investigate the barrier to resistance and mechanism(s) of action of these drugs, DENV-4 was passaged in triplicate in HEK-293 cells in the presence or absence of each drug. Resistance to ciprofloxacin was detected by the seventh passage and to difloxacin by the tenth, whereas resistance to enoxacin did not occur within ten passages. Two putative resistance-conferring mutations were detected in the envelope gene of ciprofloxacin and difloxacin-resistant DENV-4. In the absence of ciprofloxacin, ciprofloxacin-resistant viruses sustained a significantly higher viral titer than control viruses in HEK-293 and HuH-7 cells and resistant viruses were more stable than control viruses at 37 °C. These results suggest that the mechanism of action of ciprofloxacin and difloxacin involves interference with virus binding or entry.
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Affiliation(s)
- Stacey L P Scroggs
- Department of Biology, New Mexico State University, Las Cruces, NM, USA.
| | - Jordan T Gass
- Department of Biology, New Mexico State University, Las Cruces, NM, USA
| | - Ramesh Chinnasamy
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA
| | - Steven G Widen
- Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Sasha R Azar
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Shannan L Rossi
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA
| | - Nikos Vasilakis
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Tropical Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Kathryn A Hanley
- Department of Biology, New Mexico State University, Las Cruces, NM, USA
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Tiwari SK, Dang JW, Lin N, Qin Y, Wang S, Rana TM. Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC. EMBO Rep 2020; 21:e49183. [PMID: 33073500 PMCID: PMC7726779 DOI: 10.15252/embr.201949183] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/07/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Zika virus (ZIKV) is an emerging flavivirus, which when passed through vertical transmission from mother to developing fetus can lead to developmental abnormalities, including microcephaly. While there is mounting evidence that suggests a causal relationship between ZIKV infection and microcephaly, the mechanisms by which ZIKV induces these changes remain to be elucidated. Here, we demonstrate that ZIKV infection of neural stems cells, both in vitro and in vivo, induces macroautophagy to enhance viral replication. At the same time, ZIKV downregulates a number of essential selective autophagy genes, including the Fanconi anemia (FA) pathway genes. Bioinformatics analyses indicate that the transcription factor E2F4 promotes FANCC expression and is downregulated upon ZIKV infection. Gain and loss of function assays indicate that FANCC is essential for selective autophagy and acts as a negative regulator of ZIKV replication. Finally, we show that Fancc KO mice have increased ZIKV infection and autophagy protein levels in various brain regions. Taken together, ZIKV downregulates FANCC to modulate the host antiviral response and simultaneously attenuate neuronal growth.
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Affiliation(s)
- Shashi Kant Tiwari
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
| | - Jason W Dang
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
| | - Nianwei Lin
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
| | - Yue Qin
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
- Bioinformatics ProgramUniversity of California San DiegoLa JollaCAUSA
| | - Shaobo Wang
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
| | - Tariq M Rana
- Division of GeneticsDepartment of PediatricsInstitute for Genomic MedicineProgram in ImmunologyUniversity of California San DiegoLa JollaCAUSA
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33
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Jiang L, Sun Q. The Role of Autophagy-Mediated Dengue Virus Antibody-Dependent Enhancement Infection of THP-1 Cells. Intervirology 2020; 63:57-65. [PMID: 33202415 DOI: 10.1159/000511420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 09/04/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is identified as the main risk factor of severe dengue diseases. The underlying mechanisms leading to severe dengue fever remain unclear. METHODS THP-1 cells were treated with an autophagy inducer (rapamycin) or inhibitor (3-methyladenine [3-MA]) and infected with DENV and DENV-ADE. In order to investigate the expression profile of autophagy-related genes in DENV-ADE and DENV direct infection of THP-1 cells, the PCR array including 84 autophagy-related genes was selected to detect the expression of related genes, and then heat map and clustergram were established by analysis software to compare the expression differences of these genes between the DENV-ADE and DENV direct infection. RESULTS Autophagy-inducing complex related genes ATG5 and ATG12 were upregulated, and autophagosomes were also observed by transmission electron microscopy among DENV-ADE- and DENV-infected THP-1 cells, which indicated that autophagy was involved in dengue infection. The results show that 3-MA has a significant inhibitory effect on ATG12 in THP-1 cells; on the contrary, the expression of ATG12 was upreg-ulated in THP-1 cells that were treated with rapamycin. The autophagy-related genes ESR1, INS, BNIP3, FAS, TGM2, ATG9B, and DAPK1 exhibited significant differences between DENV-ADE and DENV direct infection groups. CONCLUSION In the present study, an additional mechanism of autophagy was inhibited by the autophagy inhibitor (3-MA) in DENV- and DENV-ADE-infected THP-1 cells. Our finding provided a clear link between autophagy and antibody-enhanced infection of DENV.
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Affiliation(s)
- Liming Jiang
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, China.,School of Marine Sciences, Ningbo University, Ningbo, China
| | - Qiangming Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China, .,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, China,
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A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity. mBio 2020; 11:mBio.02839-20. [PMID: 33173007 PMCID: PMC7667029 DOI: 10.1128/mbio.02839-20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Inhibitors of the dengue proteinase NS2B/3, the dengue capsid, and the host autophagy pathway were used as query compounds. Three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity, and display strong antiviral activity in cultured cells were selected for further analysis. Pyrimethamine (50% inhibitory concentration [IC50] = 1.2 μM), like the dengue proteinase inhibitor ARDP0006 to which it shows structural similarity, inhibited intramolecular NS2B/3 cleavage. Lack of toxicity early in infection allowed testing in mice, in which pyrimethamine also reduced viral loads. Niclosamide (IC50 = 0.28 μM), like dengue core inhibitor ST-148, affected structural components of the virion and inhibited early processes during infection. Vandetanib (IC50 = 1.6 μM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening.IMPORTANCE No antiviral therapeutics are currently available for dengue virus infections. By computationally overlaying the three-dimensional (3D) chemical structures of compounds known to inhibit dengue virus over those of compounds known to be safe in humans, we identified three FDA-approved compounds that are attractive candidates for repurposing as antivirals. We identified targets for two previously identified antiviral compounds and revealed a previously unknown potential anti-dengue compound, vandetanib. This computational approach to analyze a highly curated library of structures has the benefits of speed and cost efficiency. It also leverages mechanistic work with query compounds used in biomedical research to provide strong hypotheses for the antiviral mechanisms of the safer hit compounds. This workflow to identify compounds with known safety profiles can be expanded to any biological activity for which a small-molecule query compound has been identified, potentially expediting the translation of basic research to clinical interventions.
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Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles. Nat Commun 2020; 11:5189. [PMID: 33060596 PMCID: PMC7564011 DOI: 10.1038/s41467-020-19028-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Abstract
Among the various host cellular processes that are hijacked by flaviviruses, few mechanisms have been described with regard to viral egress. Here we investigate how flaviviruses exploit Src family kinases (SFKs) for exit from infected cells. We identify Lyn as a critical component for secretion of Dengue and Zika infectious particles and their corresponding virus like particles (VLPs). Pharmacological inhibition or genetic depletion of the SFKs, Lyn in particular, block virus secretion. Lyn−/− cells are impaired in virus release and are rescued when reconstituted with wild-type Lyn, but not a kinase- or palmitoylation-deficient Lyn mutant. We establish that virus particles are secreted in two distinct populations – one as free virions and the other enclosed within membranes. Lyn is critical for the latter, which consists of proteolytically processed, infectious virus progenies within autophagosome-derived vesicles. This process depends on Ulk1, Rab GTPases and SNARE complexes implicated in secretory but not degradative autophagy and occur with significantly faster kinetics than the conventional secretory pathway. Our study reveals a previously undiscovered Lyn-dependent exit route of flaviviruses in LC3+ secretory organelles that enables them to evade circulating antibodies and might affect tissue tropism. Egress of flaviviruses and involved host pathways are not well understood. Here, the authors show that Lyn is a critical host kinase for Dengue and Zika virus egress resulting in infectious virus progenies within autophagosome-derived vesicles, which might help the virus to evade antibody responses.
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36
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Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Res 2020; 182:104922. [DOI: 10.1016/j.antiviral.2020.104922] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/11/2020] [Accepted: 08/18/2020] [Indexed: 12/22/2022]
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Dubey KK, Indu, Sharma M. Reprogramming of antibiotics to combat antimicrobial resistance. Arch Pharm (Weinheim) 2020; 353:e2000168. [DOI: 10.1002/ardp.202000168] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/04/2020] [Accepted: 07/11/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Kashyap K. Dubey
- Bioprocess Engineering Laboratory, Department of Biotechnology Central University of Haryana Mahendergarh Haryana India
- School of Biotechnology Jawaharlal Nehru University New Delhi India
| | - Indu
- Bioprocess Engineering Laboratory, Department of Biotechnology Central University of Haryana Mahendergarh Haryana India
| | - Manisha Sharma
- Bioprocess Engineering Laboratory, Department of Biotechnology Central University of Haryana Mahendergarh Haryana India
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Cyclin-Dependent Kinases 8 and 19 Regulate Host Cell Metabolism during Dengue Virus Serotype 2 Infection. Viruses 2020; 12:v12060654. [PMID: 32560467 PMCID: PMC7354599 DOI: 10.3390/v12060654] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/15/2020] [Accepted: 06/15/2020] [Indexed: 12/17/2022] Open
Abstract
Dengue virus infection is associated with the upregulation of metabolic pathways within infected cells. This effect is common to infection by a broad array of viruses. These metabolic changes, including increased glucose metabolism, oxidative phosphorylation and autophagy, support the demands of viral genome replication and infectious particle formation. The mechanisms by which these changes occur are known to be, in part, directed by viral nonstructural proteins that contact and control cellular structures and metabolic enzymes. We investigated the roles of host proteins with overarching control of metabolic processes, the transcriptional regulators, cyclin-dependent kinase 8 (CDK8) and its paralog, CDK19, as mediators of virally induced metabolic changes. Here, we show that expression of CDK8, but not CDK19, is increased during dengue virus infection in Huh7 human hepatocellular carcinoma cells, although both are required for efficient viral replication. Chemical inhibition of CDK8 and CDK19 with Senexin A during infection blocks virus-induced expression of select metabolic and autophagic genes, hexokinase 2 (HK2) and microtubule-associated protein 1 light chain 3 (LC3), and reduces viral genome replication and infectious particle production. The results further define the dependence of virus replication on increased metabolic capacity in target cells and identify CDK8 and CDK19 as master regulators of key metabolic genes. The common inhibition of CDK8 and CDK19 offers a host-directed therapeutic intervention that is unlikely to be overcome by viral evolution.
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Brackney DE, Correa MA, Cozens DW. The impact of autophagy on arbovirus infection of mosquito cells. PLoS Negl Trop Dis 2020; 14:e0007754. [PMID: 32421713 PMCID: PMC7259790 DOI: 10.1371/journal.pntd.0007754] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 05/29/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022] Open
Abstract
Macroautophagy is an evolutionarily conserved cellular process critical for maintaining cellular homeostasis. It can additionally function as an innate immune response to viral infection as has been demonstrated for a number of arthropod-borne (arbo-) viruses. Arboviruses are maintained in a transmission cycle between vertebrate hosts and invertebrate vectors yet the majority of studies assessing autophagy-arbovirus interactions have been limited to the mammalian host. Therefore we evaluated the role of autophagy during arbovirus infection of the invertebrate vector using the tractable Aag2 Aedes aegypti mosquito cell culture system. Our data demonstrates that autophagy is significantly induced in mosquito cells upon infection with two divergent arboviruses: dengue virus-2 (DENV-2; Flaviviridae, Flavivirus) and chikungunya virus (CHIKV; Togaviridae, Alphavirus). While assessing the role of autophagy during arbovirus infection, we observed a somewhat paradoxical outcome. Both induction and suppression of autophagy via torin-1 and spautin-1, respectively, resulted in increased viral titers for both viruses, yet suppression of autophagy-related genes had no effect. Interestingly, chemical modulators of autophagy had either no effect or opposite effects in another widely used mosquito cell line, C6/36 Aedes albopictus cells. Together, our data reveals a limited role for autophagy during arbovirus infection of mosquito cells. Further, our findings suggest that commonly used chemical modulators of autophagy alter mosquito cells in such a way as to promote viral replication; however, it is unclear if this occurs directly through autophagic manipulation or other means.
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Affiliation(s)
- Doug E. Brackney
- Center for Vector-Borne and Zoonotic Diseases, Department of Environmental Sciences, The Connecticut Agricultural Experiment Station, New Haven, Connecticut, United States of America
| | - Maria A. Correa
- Center for Vector-Borne and Zoonotic Diseases, Department of Environmental Sciences, The Connecticut Agricultural Experiment Station, New Haven, Connecticut, United States of America
| | - Duncan W. Cozens
- Center for Vector-Borne and Zoonotic Diseases, Department of Environmental Sciences, The Connecticut Agricultural Experiment Station, New Haven, Connecticut, United States of America
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40
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Wong HH, Sanyal S. Manipulation of autophagy by (+) RNA viruses. Semin Cell Dev Biol 2020; 101:3-11. [PMID: 31382014 PMCID: PMC7102625 DOI: 10.1016/j.semcdb.2019.07.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/11/2019] [Accepted: 07/30/2019] [Indexed: 01/07/2023]
Abstract
Autophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention.
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Affiliation(s)
- Ho Him Wong
- HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong
| | - Sumana Sanyal
- HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong,School of Biomedical Sciences, LKS Faculty of Medicine, University of Hong Kong, Hong Kong,Corresponding author at: HKU-Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong
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Diosa-Toro M, Prasanth KR, Bradrick SS, Garcia Blanco MA. Role of RNA-binding proteins during the late stages of Flavivirus replication cycle. Virol J 2020; 17:60. [PMID: 32334603 PMCID: PMC7183730 DOI: 10.1186/s12985-020-01329-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 04/11/2020] [Indexed: 12/21/2022] Open
Abstract
The genus Flavivirus encompasses several worldwide-distributed arthropod-borne viruses including, dengue virus, Japanese encephalitis virus, West Nile virus, yellow fever virus, Zika virus, and tick-borne encephalitis virus. Infection with these viruses manifest with symptoms ranging from febrile illness to life- threatening hypotensive shock and encephalitis. Therefore, flaviviruses pose a great risk to public health. Currently, preventive measures are falling short to control epidemics and there are no antivirals against any Flavivirus.Flaviviruses carry a single stranded positive-sense RNA genome that plays multiple roles in infected cells: it is translated into viral proteins, used as template for genome replication, it is the precursor of the subgenomic flaviviral RNA and it is assembled into new virions. Furthermore, viral RNA genomes are also packaged into extracellular vesicles, e.g. exosomes, which represent an alternate mode of virus dissemination.Because RNA molecules are at the center of Flavivirus replication cycle, viral and host RNA-binding proteins (RBPs) are critical determinants of infection. Numerous studies have revealed the function of RBPs during Flavivirus infection, particularly at the level of RNA translation and replication. These proteins, however, are also critical participants at the late stages of the replication cycle. Here we revise the function of host RBPs and the viral proteins capsid, NS2A and NS3, during the packaging of viral RNA and the assembly of new virus particles. Furthermore, we go through the evidence pointing towards the importance of host RBPs in mediating cellular RNA export with the idea that the biogenesis of exosomes harboring Flavivirus RNA would follow an analogous pathway.
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Affiliation(s)
- Mayra Diosa-Toro
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
| | - K Reddisiva Prasanth
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Shelton S Bradrick
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA
- Global Health, Surveillance & Diagnostics Group, MRIGlobal, Kansas City, MO, USA
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
| | - Mariano A Garcia Blanco
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
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Evans AS, Lennemann NJ, Coyne CB. BPIFB3 Regulates Endoplasmic Reticulum Morphology To Facilitate Flavivirus Replication. J Virol 2020; 94:e00029-20. [PMID: 32102874 PMCID: PMC7163128 DOI: 10.1128/jvi.00029-20] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 02/14/2020] [Indexed: 12/20/2022] Open
Abstract
Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection.IMPORTANCE Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.
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Affiliation(s)
- Azia S Evans
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Center for Microbial Pathogenesis, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nicholas J Lennemann
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Center for Microbial Pathogenesis, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Carolyn B Coyne
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Center for Microbial Pathogenesis, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Richard K. Mellon Institute for Pediatric Research, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
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43
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Hu Z, Pan Y, Cheng A, Zhang X, Wang M, Chen S, Zhu D, Liu M, Yang Q, Wu Y, Zhao X, Huang J, Zhang S, Mao S, Ou X, Yu Y, Zhang L, Liu Y, Tian B, Pan L, Rehman MU, Yin Z, Jia R. Autophagy Is a Potential Therapeutic Target Against Duck Tembusu Virus Infection in vivo. Front Cell Infect Microbiol 2020; 10:155. [PMID: 32351903 PMCID: PMC7174708 DOI: 10.3389/fcimb.2020.00155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 03/24/2020] [Indexed: 12/18/2022] Open
Abstract
Duck tembusu virus (DTMUV) is newly emerged in poultry and causes great losses to the breeding industry in China and neighboring countries. Effective antiviral strategies are still being studied. Autophagy is a cellular degradative pathway, and our lab's previous data show that autophagy promotes DTMUV replication in vitro. To study the role of autophagy further in vivo, we utilized ducks as the animal model to investigate the autophagy responses in DTMUV-targeted tissues. And also, we utilized autophagy regulators, including Rapamycin (Rapa) as the autophagy enhancer, 3-Methyladenine (3-MA) and Chloroquine (CQ) as the autophagy inhibitors, to adjust the host autophagic levels and then study the effects of autophagy on tissue damages and virus replication. As a result, we first found DTMUV infection trigged autophagy and autophagy regulator treatments regulated autophagy levels successfully in duck spleens and brains. Next, we found that autophagy inhibitors inhibited DTMUV replication and alleviated DTMUV-induced pathological symptoms, whereas the autophagy inducer treatment led to the opposite effects. And we also found that autophagic regulation was correlated with the expression of innate immune genes, including pattern recognition receptors, type I interferons, and cytokines, and caused different effects in different tissues. In summary, we demonstrated that autophagy facilitated DTMUV replication, aggravated the developments of pathological symptoms and possibly counteracts the host's innate immunity response in vivo.
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Affiliation(s)
- Zhiqiang Hu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Yuhong Pan
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Xingcui Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Dekang Zhu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Xinxin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Juan Huang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Bin Tian
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Leichang Pan
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Mujeeb Ur Rehman
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, China.,Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Wenjiang, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, China
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44
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Echavarria-Consuegra L, Smit JM, Reggiori F. Role of autophagy during the replication and pathogenesis of common mosquito-borne flavi- and alphaviruses. Open Biol 2020; 9:190009. [PMID: 30862253 PMCID: PMC6451359 DOI: 10.1098/rsob.190009] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Arboviruses that are transmitted to humans by mosquitoes represent one of the most important causes of febrile illness worldwide. In recent decades, we have witnessed a dramatic re-emergence of several mosquito-borne arboviruses, including dengue virus (DENV), West Nile virus (WNV), chikungunya virus (CHIKV) and Zika virus (ZIKV). DENV is currently the most common mosquito-borne arbovirus, with an estimated 390 million infections worldwide annually. Despite a global effort, no specific therapeutic strategies are available to combat the diseases caused by these viruses. Multiple cellular pathways modulate the outcome of infection by either promoting or hampering viral replication and/or pathogenesis, and autophagy appears to be one of them. Autophagy is a degradative pathway generally induced to counteract viral infection. Viruses, however, have evolved strategies to subvert this pathway and to hijack autophagy components for their own benefit. In this review, we will focus on the role of autophagy in mosquito-borne arboviruses with emphasis on DENV, CHIKV, WNV and ZIKV, due to their epidemiological importance and high disease burden.
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Affiliation(s)
- Liliana Echavarria-Consuegra
- 1 Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen , Groningen , The Netherlands
| | - Jolanda M Smit
- 1 Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen , Groningen , The Netherlands
| | - Fulvio Reggiori
- 2 Department of Cell Biology, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
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45
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Schein CH. Repurposing approved drugs on the pathway to novel therapies. Med Res Rev 2020; 40:586-605. [PMID: 31432544 PMCID: PMC7018532 DOI: 10.1002/med.21627] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 07/17/2019] [Accepted: 07/26/2019] [Indexed: 12/22/2022]
Abstract
The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many "repurposed" drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic-resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the "cytokine storm" response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.
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Affiliation(s)
- Catherine H Schein
- Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity (IHII), University of Texas Medical Branch at Galveston, Galveston, Texas
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46
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Tao S, Drexler I. Targeting Autophagy in Innate Immune Cells: Angel or Demon During Infection and Vaccination? Front Immunol 2020; 11:460. [PMID: 32265919 PMCID: PMC7096474 DOI: 10.3389/fimmu.2020.00460] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/28/2020] [Indexed: 01/07/2023] Open
Abstract
Innate immune cells are the "doorkeepers" in the immune system and are important for the initiation of protective vaccine responses against infection. Being an essential regulatory component of the immune system in these cells, autophagy not only mediates pathogen clearance and cytokine production, but also balances the immune response by preventing harmful overreaction. Interestingly, recent literature indicates that autophagy is positively or negatively regulating the innate immune response in a cell type-specific manner. Moreover, autophagy serves as a bridge between innate and adaptive immunity. It is involved in antigen presentation by delivering pathogen compounds to B and T cells, which is important for effective immune protection. Upon infection, autophagy can also be hijacked by some pathogens for replication or evade host immune responses. As a result, autophagy seems like a double-edged sword to the immune response, strongly depending on the cell types involved and infection models used. In this review, the dual role of autophagy in regulating the immune system will be highlighted in various infection models with particular focus on dendritic cells, monocytes/macrophages and neutrophils. Targeting autophagy in these cells as for therapeutic application or prophylactic vaccination will be discussed considering both roles of autophagy, the "angel" enhancing innate immune responses, antigen presentation, pathogen clearance and dampening inflammation or the "demon" enabling viral replication and degrading innate immune components. A better understanding of this dual potential will help to utilize autophagy in innate immune cells in order to optimize vaccines or treatments against infectious diseases.
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47
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Abstract
Autophagy is an intracellular recycling process that maintains cellular homeostasis by orchestrating immunity upon viral infection. Following viral infection, autophagy is often initiated to curtail infection by delivering viral particles for lysosomal degradation and further integrating with innate pattern recognition receptor signaling to induce interferon (IFN)-mediated viral clearance. However, some viruses have evolved anti-autophagy strategies to escape host immunity and to promote viral replication. In this chapter, we illustrate how autophagy prevents viral infection to generate an optimal anti-viral milieu, and then concentrate on how viruses subvert and hijack the autophagic process to evade immunosurveillance, thereby facilitating viral replication and pathogenesis. Understanding the interplays between autophagy and viral infection is anticipated to guide the development of effective anti-viral therapeutics to fight against infectious diseases.
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48
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TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy. Int J Mol Sci 2019; 20:ijms20194893. [PMID: 31581681 PMCID: PMC6801812 DOI: 10.3390/ijms20194893] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/29/2019] [Accepted: 09/29/2019] [Indexed: 12/22/2022] Open
Abstract
Dengue virus (DENV) infection triggers the activation of autophagy to facilitate the viral replication cycle from various aspects. Although a number of stimulators are proposed to activate autophagy, none of them appears prior to the uncoating process. Given that T-cell immunoglobulin and mucin domain 1 (TIM-1) receptor is a putative DENV receptor and promotes apoptotic body clearance by autophagy induction, it raises the possibility that TIM-1 may participate in the activation of DENV-induced autophagy. In this study, confocal images first revealed the co-localization of TIM-1 with autophagosomes in DENV-induced autophagy rather than rapamycin-induced autophagy, suggesting the co-transportation of TIM-1 with DENV during infection. The treatment of siRNA to knockdown TIM-1 expression in DENV-infected GFP-microtubule-associated protein light chain 3 (LC3)-Huh7.5 cells revealed that TIM-1 is required not only for DENV cellular internalization but also for autophagy activation. Furthermore, knockdown p85, a subunit of phosphoinositide 3-kinases (PI3Ks), which is co-localized with TIM-1 at rab5-positive endosomes caused the reduction of autophagy, indicating that TIM-1-mediated DENV-induced autophagy requires p85. Taken together, the current study uncovered TIM-1 as a novel factor for triggering autophagy in DENV infection through TIM-1-p85 axis, in addition to serving as a DENV receptor.
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49
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Ahammad F, Tengku Abd Rashid TR, Mohamed M, Tanbin S, Ahmad Fuad FA. Contemporary Strategies and Current Trends in Designing Antiviral Drugs against Dengue Fever via Targeting Host-Based Approaches. Microorganisms 2019; 7:E296. [PMID: 31466307 PMCID: PMC6780377 DOI: 10.3390/microorganisms7090296] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Dengue virus (DENV) is an arboviral human pathogen transmitted through mosquito bite that infects an estimated ~400 million humans (~5% of the global population) annually. To date, no specific therapeutics have been developed that can prevent or treat infections resulting from this pathogen. DENV utilizes numerous host molecules and factors for transcribing the single-stranded ~11 kb positive-sense RNA genome. For example, the glycosylation machinery of the host is required for viral particles to assemble in the endoplasmic reticulum. Since a variety of host factors seem to be utilized by the pathogens, targeting these factors may result in DENV inhibitors, and will play an important role in attenuating the rapid emergence of other flaviviruses. Many experimental studies have yielded findings indicating that host factors facilitate infection, indicating that the focus should be given to targeting the processes contributing to pathogenesis along with many other immune responses. Here, we provide an extensive literature review in order to elucidate the progress made in the development of host-based approaches for DENV viral infections, focusing on host cellular mechanisms and factors responsible for viral replication, aiming to aid the potential development of host-dependent antiviral therapeutics.
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Affiliation(s)
- Foysal Ahammad
- Department of Biotechnology Engineering, International Islamic University Malaysia, Kuala Lumpur 50728, Malaysia
| | | | - Maizan Mohamed
- Faculty of Veterinary Medicine, Universiti Malaysia Kelantan, Locked Bag 36, Pengkalan Chepa, Kota Bharu 16100, Kelantan, Malaysia
| | - Suriyea Tanbin
- Department of Biotechnology Engineering, International Islamic University Malaysia, Kuala Lumpur 50728, Malaysia
| | - Fazia Adyani Ahmad Fuad
- Department of Biotechnology Engineering, International Islamic University Malaysia, Kuala Lumpur 50728, Malaysia.
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50
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Flaviviridae Viruses and Oxidative Stress: Implications for Viral Pathogenesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1409582. [PMID: 31531178 PMCID: PMC6720866 DOI: 10.1155/2019/1409582] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/09/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023]
Abstract
Oxidative stress is induced once the balance of generation and neutralization of reactive oxygen species (ROS) is broken in the cell, and it plays crucial roles in a variety of natural and diseased processes. Infections of Flaviviridae viruses trigger oxidative stress, which affects both the cellular metabolism and the life cycle of the viruses. Oxidative stress associated with specific viral proteins, experimental culture systems, and patient infections, as well as its correlations with the viral pathogenesis attracts much research attention. In this review, we primarily focus on hepatitis C virus (HCV), dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV) as representatives of Flaviviridae viruses and we summarize the mechanisms involved in the relevance of oxidative stress for virus-associated pathogenesis. We discuss the current understanding of the pathogenic mechanisms of oxidative stress induced by Flaviviridae viruses and highlight the relevance of autophagy and DNA damage in the life cycle of viruses. Understanding the crosstalk between viral infection and oxidative stress-induced molecular events may offer new avenues for antiviral therapeutics.
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