1
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-like receptor response to Zika virus infection: progress toward infection control. NPJ VIRUSES 2025; 3:20. [PMID: 40295746 PMCID: PMC11906774 DOI: 10.1038/s44298-025-00102-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/19/2025] [Indexed: 04/30/2025]
Abstract
Infection with the Zika virus (ZIKV) poses a threat to human health. An improved understanding of the host Toll-like receptor response, disease onset, and viral clearance in vivo and in vitro may lead to the development of therapeutic or prophylactic interventions against viral infections. Currently, no clinically approved ZIKV vaccine is available, highlighting the need for its development. In this study, we discuss the progress in the Zika vaccine, including advances in the use of Toll-like receptor agonists as vaccine adjuvants to enhance vaccine efficacy.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, Bangladesh.
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
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2
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Huang Y, Yan X, Chu X, Shi Y, Xiang J, Yang S. Duck Tembusu virus induced mitophagy in vacuolate spermatogenic cells is mediated by PINK1-Parkin pathway. Poult Sci 2025; 104:104795. [PMID: 39823839 PMCID: PMC11786760 DOI: 10.1016/j.psj.2025.104795] [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: 10/17/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 01/20/2025] Open
Abstract
As a significant emerging and re-emerging pathogen in China, the widely spread of Duck Tembusu virus (DTMUV) caused enormous economic losses to poultry industry. On account of DTMUV diseases' main symptoms on haemorrhagic oophoritis, intensive attentions were focused on female reproductive organ. Nevertheless, the DTMUV infection of sperm and testis manifested that testis was an important vector for vertical transmission of DTMUV. In the present study, histopathology, immunofluorescence and transmission electron microscopy (TEM) analysis of DTMUV-infected duck testis revealed that DTMUV infection induced seminiferous epithelium injury via spermatogenic cells vacuolization. After DTMUV infection, the expression of autophagy-related genes and proteins in testis were significantly up-regulated. Further TEM analysis discovered that different stages of autophagic and mitophagy structures were visible in cytoplasm of spermatogenic cells after DTMUV infection. And more notably, the testicular protein expression of PINK1 and Parkin were significantly increased after DTMUV infection. In summary, our study discovered that, after DTMUV infection, PINK1-Parkin pathway mediated mitophagy were activated and then induced spermatogenic cells vacuolization.
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Affiliation(s)
- Yufei Huang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China; Guangling College, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China
| | - Xiaoman Yan
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China
| | - Xiaoya Chu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Yonghong Shi
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, PR China
| | - Jacob Xiang
- Clinical Pharmacist, Foothills Medical Centre, 140329St NW Calgary Alberta Canada T2N 2T9
| | - Sheng Yang
- Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu Province 225009, PR China.
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3
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Wang Y, Song D, Li Y, Qin L, Wan Q, Hu H, Wu M, Feng Y, Schang L, Weiss R, He ML. Erp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation. Emerg Microbes Infect 2024; 13:2417864. [PMID: 39404735 PMCID: PMC11520102 DOI: 10.1080/22221751.2024.2417864] [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: 06/20/2024] [Revised: 09/13/2024] [Accepted: 10/13/2024] [Indexed: 10/29/2024]
Abstract
It is believed that DNA double-strand breaks induced by Zika virus (ZIKV) infection in pregnant women is a main reason of brain damage (e.g. microcephaly, severe brain malformation, and neuropathy) in newborn babies [1,2], but its underlying mechanism is poorly understood. In this study, we report that the depletion of ERp57, a member of the protein disulphide isomerase (PDI) family, leads to the limited production of ZIKV in nerve cells. ERp57 knockout not only suppresses viral induced reactive oxygen species (ROS) mediated host DNA damage, but also decreases apoptosis. Strikingly, DNA damage depends on ERp57-bridged complex formation of viral protein NS2B/NS3. LOC14, an ERp57 inhibitor, restricts ZIKV infection and virus-induced DNA damage. Our work reveals an important role of ERp57 in both ZIKV propagation and virus-induced DNA damage, suggesting a potential target against ZIKV infection.
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Affiliation(s)
- Yiran Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Dan Song
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Yichen Li
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Leiying Qin
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Qianya Wan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Huan Hu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Mandi Wu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Yaxiu Feng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Luis Schang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Robert Weiss
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
- CityU Shenzhen Research Institute, Shenzhen, People’s Republic of China
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4
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Huang L, Liu L, Zhu J, Chen N, Chen J, Chan CF, Gao F, Yin Y, Sun J, Zhang R, Zhang K, Qi W, Yue J. Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy. Virol Sin 2024; 39:892-908. [PMID: 39251138 PMCID: PMC11738800 DOI: 10.1016/j.virs.2024.09.001] [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: 05/26/2024] [Accepted: 08/29/2024] [Indexed: 09/11/2024] Open
Abstract
Flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV), represent a substantial public health challenge as there are currently no approved treatments available. Here, we investigated the antiviral effects of bis-benzylisoquinoline alkaloids (BBAs) on flavivirus infections. We evaluated five specific BBAs-berbamine, tetrandrine, iso-tetrandrine, fangchinoline, and cepharanthine-and found that they effectively inhibited infections by ZIKV, DENV, or JEV by blocking virus entry and genome replication stages in the flavivirus life cycle. Furthermore, we synthesized a fluorophore-conjugated BBA and showed that BBAs targeted endolysosomes, causing lysosomal pH alkalization. Mechanistic studies on inhibiting ZIKV infection by BBAs revealed that these compounds blocked TRPML channels, leading to lysosomal dysfunction and reducing the expression of NCAM1, a key receptor for the entry of ZIKV into cells, thereby decreasing cells susceptibility to ZIKV infection. Additionally, BBAs inhibited the fusion of autophagosomes and lysosomes, significantly reducing viral RNA replication. Collectively, our results suggest that BBAs inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy, respectively, underscoring the potential of BBAs as therapeutic agents against flavivirus infections.
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Affiliation(s)
- Lihong Huang
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Lele Liu
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Junhai Zhu
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Nanjun Chen
- Department of Computer Science, City University of Hong Kong, Hong Kong, 999077, China
| | - Jie Chen
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China
| | - Chuen-Fuk Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China
| | - Fei Gao
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Youqin Yin
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Jiufeng Sun
- Guangdong Workstation for Emerging Infectious Disease Control and Prevention, Guangdong Provincial Key Laboratory of Pathogen Detection for Emerging Infectious Disease Response, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
| | - Rongxin Zhang
- Laboratory of Immunology and Inflammation, Institute of Basic Medical Sciences and Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Kehui Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
| | - Wenbao Qi
- State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China.
| | - Jianbo Yue
- City University of Hong Kong Shenzhen Research Institute, Shenzhen, 518057, China; Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Global Health Research Center, Duke Kunshan University, Kunshan, 215316, China; College of Life Sciences, Wuhan University, Wuhan, 430072, China.
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5
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Bindu, Pandey HS, Seth P. Interplay Between Zika Virus-Induced Autophagy and Neural Stem Cell Fate Determination. Mol Neurobiol 2024; 61:9927-9944. [PMID: 37910284 DOI: 10.1007/s12035-023-03704-1] [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: 04/14/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023]
Abstract
The Zika virus (ZIKV) outbreaks and its co-relation with microcephaly have become a global health concern. It is primarily transmitted by a mosquito, but can also be transmitted from an infected mother to her fetus causing impairment in brain development, leading to microcephaly. However, the underlying molecular mechanism of ZIKV-induced microcephaly is poorly understood. In this study, we explored the role of ZIKV non-structural protein NS4A and NS4B in ZIKV pathogenesis in a well-characterized primary culture of human fetal neural stem cells (fNSCs). We observed that the co-transfection of NS4A and NS4B altered the neural stem cell fate by arresting proliferation and inducing premature neurogenesis. NS4A + NS4B transfection in fNSCs increased autophagy and dysregulated notch signaling. Further, it also altered the regulation of downstream genes controlling cell proliferation. Additionally, we reported that 3 methyl-adenine (3-MA), a potent autophagy inhibitor, attenuated the deleterious effects of NS4A and NS4B as evidenced by the rescue in Notch1 expression, enhanced proliferation, and reduced premature neurogenesis. Our attempts to understand the mechanism of autophagy induction indicate the involvement of mitochondrial fission and ROS. Collectively, our findings highlight the novel role of NS4A and NS4B in mediating NSC fate alteration through autophagy-mediated notch degradation. The study also helps to advance our understanding of ZIKV-induced neuropathogenesis and suggests autophagy as a potential target for anti-ZIKV therapeutic intervention.
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Affiliation(s)
- Bindu
- Department of Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurgaon, Haryana, 122052, India
| | - Hriday Shanker Pandey
- Department of Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurgaon, Haryana, 122052, India
| | - Pankaj Seth
- Department of Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurgaon, Haryana, 122052, India.
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Palmero Casanova B, Albentosa González L, Maringer K, Sabariegos R, Mas A. A conserved role for AKT in the replication of emerging flaviviruses in vertebrates and vectors. Virus Res 2024; 348:199447. [PMID: 39117146 PMCID: PMC11364138 DOI: 10.1016/j.virusres.2024.199447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/11/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
One third of all emerging infectious diseases are vector-borne, with no licensed antiviral therapies available against any vector-borne viruses. Zika virus and Usutu virus are two emerging flaviviruses transmitted primarily by mosquitoes. These viruses modulate different host pathways, including the PI3K/AKT/mTOR pathway. Here, we report the effect on ZIKV and USUV replication of two AKT inhibitors, Miransertib (ARQ-092, allosteric inhibitor) and Capivasertib (AZD5363, competitive inhibitor) in different mammalian and mosquito cell lines. Miransertib showed a stronger inhibitory effect against ZIKV and USUV than Capivasertib in mammalian cells, while Capivasertib showed a stronger effect in mosquito cells. These findings indicate that AKT plays a conserved role in flavivirus infection, in both the vertebrate host and invertebrate vector. Nevertheless, the specific function of AKT may vary depending on the host species. These findings indicate that AKT may be playing a conserved role in flavivirus infection in both, the vertebrate host and the invertebrate vector. However, the specific function of AKT may vary depending on the host species. A better understanding of virus-host interactions is therefore required to develop new treatments to prevent human disease and new approaches to control transmission by insect vectors.
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Affiliation(s)
- Blanca Palmero Casanova
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain
| | - Laura Albentosa González
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Facultad de farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02008 Albacete, Spain
| | - Kevin Maringer
- The Pirbright Institute, Ash Road, Pirbright, Surrey GU24 0NF, UK
| | - Rosario Sabariegos
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Unidad asociada de Biomedicina UCLM-CSIC. Universidad de Castilla-La Mancha. C/Altagracia 50, 13071 Ciudad Real, Spain; Facultad de Medicina, Universidad de Castilla-La Mancha. C/Almansa 14, 02008 Albacete, Spain
| | - Antonio Mas
- Instituto de Investigación Biomédica de la UCLM (IB-UCLM), C/Almansa 14, 02008 Albacete, Spain; Facultad de farmacia, Universidad de Castilla-La Mancha, Av. Dr. José María Sánchez Ibáñez, s/n, 02008 Albacete, Spain; Unidad asociada de Biomedicina UCLM-CSIC. Universidad de Castilla-La Mancha. C/Altagracia 50, 13071 Ciudad Real, Spain.
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7
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Chen L, Wei M, Zhou B, Wang K, Zhu E, Cheng Z. The roles and mechanisms of endoplasmic reticulum stress-mediated autophagy in animal viral infections. Vet Res 2024; 55:107. [PMID: 39227990 PMCID: PMC11373180 DOI: 10.1186/s13567-024-01360-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/28/2024] [Indexed: 09/05/2024] Open
Abstract
The endoplasmic reticulum (ER) is a unique organelle responsible for protein synthesis and processing, lipid synthesis in eukaryotic cells, and the replication of many animal viruses is closely related to ER. A considerable number of viral proteins are synthesised during viral infection, resulting in the accumulation of unfolded and misfolded proteins in ER, which in turn induces endoplasmic reticulum stress (ERS). ERS further drives three signalling pathways (PERK, IRE1, and ATF6) of the cellular unfolded protein response (UPR) to respond to the ERS. In numerous studies, ERS has been shown to mediate autophagy, a highly conserved cellular degradation mechanism to maintain cellular homeostasis in eukaryotic cells, through the UPR to restore ER homeostasis. ERS-mediated autophagy is closely linked to the occurrence and development of numerous viral diseases in animals. Host cells can inhibit viral replication by regulating ERS-mediated autophagy, restoring the ER's normal physiological process. Conversely, many viruses have evolved strategies to exploit ERS-mediated autophagy to achieve immune escape. These strategies include the regulation of PERK-eIF2α-Beclin1, PERK-eIF2α-ATF4-ATG12, IRE1α-JNK-Beclin1, and other signalling pathways, which provide favourable conditions for the replication of animal viruses in host cells. The ERS-mediated autophagy pathway has become a hot topic in animal virological research. This article reviews the most recent research regarding the regulatory functions of ERS-mediated autophagy pathways in animal viral infections, emphasising the underlying mechanisms in the context of different viral infections. Furthermore, it considers the future direction and challenges in the development of ERS-mediated autophagy targeting strategies for combating animal viral diseases, which will contribute to unveiling their pathogenic mechanism from a new perspective and provide a scientific reference for the discovery and development of new antiviral drugs and preventive strategies.
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Affiliation(s)
- Lan Chen
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Miaozhan Wei
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Bijun Zhou
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Kaigong Wang
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Erpeng Zhu
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China.
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China.
| | - Zhentao Cheng
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China.
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China.
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8
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Singh S, Ahmad F, Aruri H, Das S, Parajuli P, Gavande NS, Singh PK, Kumar A. Novel quinoline substituted autophagy inhibitors attenuate Zika virus replication in ocular cells. Virus Res 2024; 347:199419. [PMID: 38880335 PMCID: PMC11239713 DOI: 10.1016/j.virusres.2024.199419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/26/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024]
Abstract
Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV.
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Affiliation(s)
- Sneha Singh
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Faraz Ahmad
- Department of Ophthalmology, Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA
| | - Hariprasad Aruri
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Susmita Das
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Prahlad Parajuli
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Navnath S Gavande
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
| | - Pawan Kumar Singh
- Department of Ophthalmology, Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA.
| | - Ashok Kumar
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, USA.
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9
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Zhao C, Chen J, Liu Z, Liang H, Chen X, Cheng L, Xie S, Lin Z, Wu R, Zhao Q, Xue Y, Lai X, Jin X, Xu JF, Su X. Activation of nicotinic acetylcholine receptor α7 subunit limits Zika viral infection via promoting autophagy and ferroptosis. Mol Ther 2024; 32:2641-2661. [PMID: 38822526 PMCID: PMC11405161 DOI: 10.1016/j.ymthe.2024.05.037] [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: 12/04/2023] [Revised: 04/13/2024] [Accepted: 05/29/2024] [Indexed: 06/03/2024] Open
Abstract
Vagus nerve regulates viral infection and inflammation via the alpha 7 nicotinic acetylcholine receptor (α7 nAChR); however, the role of α7 nAChR in ZIKA virus (ZIKV) infection, which can cause severe neurological diseases such as microcephaly and Guillain-Barré syndrome, remains unknown. Here, we first examined the role of α7 nAChR in ZIKV infection in vitro. A broad effect of α7 nAChR activation was identified in limiting ZIKV infection in multiple cell lines. Combined with transcriptomics analysis, we further demonstrated that α7 nAChR activation promoted autophagy and ferroptosis pathways to limit cellular ZIKV viral loads. Additionally, activation of α7 nAChR prevented ZIKV-induced p62 nucleus accumulation, which mediated an enhanced autophagy pathway. By regulating proteasome complex and an E3 ligase NEDD4, activation of α7 nAChR resulted in increased amount of cellular p62, which further enhanced the ferroptosis pathway to reduce ZIKV infection. Moreover, utilizing in vivo neonatal mouse models, we showed that α7 nAChR is essential in controlling the disease severity of ZIKV infection. Taken together, our findings identify an α7 nAChR-mediated effect that critically contributes to limiting ZIKV infection, and α7 nAChR activation offers a novel strategy for combating ZIKV infection and its complications.
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Affiliation(s)
- Caiqi Zhao
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China; Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200000, China; University of Chinese Academy of Sciences, Beijing 100190, China
| | - Jie Chen
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100190, China; Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhihua Liu
- University of Chinese Academy of Sciences, Beijing 100190, China; Vaccine Center, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Huabin Liang
- University of Chinese Academy of Sciences, Beijing 100190, China; Vaccine Center, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Xiaoyan Chen
- Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lianping Cheng
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Shitao Xie
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Zhekai Lin
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Renlan Wu
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Qi Zhao
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Yue Xue
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Xiaoyun Lai
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China
| | - Xia Jin
- University of Chinese Academy of Sciences, Beijing 100190, China; Vaccine Center, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China.
| | - Jin-Fu Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200000, China.
| | - Xiao Su
- Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China; Vaccine Center, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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10
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Badu P, Baniulyte G, Sammons MA, Pager CT. Activation of ATF3 via the Integrated Stress Response Pathway Regulates Innate Immune Response to Restrict Zika Virus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.26.550716. [PMID: 37546954 PMCID: PMC10402074 DOI: 10.1101/2023.07.26.550716] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects from a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using CRISPR-Cas9 system to delete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. We also determined that ATF3 enhances the expression of antiviral genes such as STAT1 and other components in the innate immunity pathway to induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between the integrated stress response and innate immune response pathways and highlights an important role for ATF3 in establishing an antiviral effect during ZIKV infection.
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Affiliation(s)
- Pheonah Badu
- Department of Biological Sciences, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
- The RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
| | - Gabriele Baniulyte
- Department of Biological Sciences, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
- The RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
| | - Morgan A. Sammons
- Department of Biological Sciences, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
- The RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
| | - Cara T. Pager
- Department of Biological Sciences, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
- The RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, NY 12222
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11
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Argandona Lopez C, Brown AM. Microglial- neuronal crosstalk in chronic viral infection through mTOR, SPP1/OPN and inflammasome pathway signaling. Front Immunol 2024; 15:1368465. [PMID: 38646526 PMCID: PMC11032048 DOI: 10.3389/fimmu.2024.1368465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
HIV-infection of microglia and macrophages (MMs) induces neuronal injury and chronic release of inflammatory stimuli through direct and indirect molecular pathways. A large percentage of people with HIV-associated neurologic and psychiatric co-morbidities have high levels of circulating inflammatory molecules. Microglia, given their susceptibility to HIV infection and long-lived nature, are reservoirs for persistent infection. MMs and neurons possess the molecular machinery to detect pathogen nucleic acids and proteins to activate innate immune signals. Full activation of inflammasome assembly and expression of IL-1β requires a priming event and a second signal. Many studies have demonstrated that HIV infection alone can activate inflammasome activity. Interestingly, secreted phosphoprotein-1 (SPP1/OPN) expression is highly upregulated in the CNS of people infected with HIV and neurologic dysfunction. Interestingly, all evidence thus far suggests a protective function of SPP1 signaling through mammalian target of rapamycin (mTORC1/2) pathway function to counter HIV-neuronal injury. Moreover, HIV-infected mice knocked down for SPP1 show by neuroimaging, increased neuroinflammation compared to controls. This suggests that SPP1 uses unique regulatory mechanisms to control the level of inflammatory signaling. In this mini review, we discuss the known and yet-to-be discovered biological links between SPP1-mediated stimulation of mTOR and inflammasome activity. Additional new mechanistic insights from studies in relevant experimental models will provide a greater understanding of crosstalk between microglia and neurons in the regulation of CNS homeostasis.
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Affiliation(s)
- Catalina Argandona Lopez
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Amanda M. Brown
- Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Division of Neuroimmunology, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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12
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Pérez-Yanes S, Lorenzo-Sánchez I, Cabrera-Rodríguez R, García-Luis J, Trujillo-González R, Estévez-Herrera J, Valenzuela-Fernández A. The ZIKV NS5 Protein Aberrantly Alters the Tubulin Cytoskeleton, Induces the Accumulation of Autophagic p62 and Affects IFN Production: HDAC6 Has Emerged as an Anti-NS5/ZIKV Factor. Cells 2024; 13:598. [PMID: 38607037 PMCID: PMC11011779 DOI: 10.3390/cells13070598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Zika virus (ZIKV) infection and pathogenesis are linked to the disruption of neurogenesis, congenital Zika syndrome and microcephaly by affecting neural progenitor cells. Nonstructural protein 5 (NS5) is the largest product encoded by ZIKV-RNA and is important for replication and immune evasion. Here, we studied the potential effects of NS5 on microtubules (MTs) and autophagy flux, together with the interplay of NS5 with histone deacetylase 6 (HDAC6). Fluorescence microscopy, biochemical cell-fractionation combined with the use of HDAC6 mutants, chemical inhibitors and RNA interference indicated that NS5 accumulates in nuclear structures and strongly promotes the acetylation of MTs that aberrantly reorganize in nested structures. Similarly, NS5 accumulates the p62 protein, an autophagic-flux marker. Therefore, NS5 alters events that are under the control of the autophagic tubulin-deacetylase HDAC6. HDAC6 appears to degrade NS5 by autophagy in a deacetylase- and BUZ domain-dependent manner and to control the cytoplasmic expression of NS5. Moreover, NS5 inhibits RNA-mediated RIG-I interferon (IFN) production, resulting in greater activity when autophagy is inhibited (i.e., effect correlated with NS5 stability). Therefore, it is conceivable that NS5 contributes to cell toxicity and pathogenesis, evading the IFN-immune response by overcoming HDAC6 functions. HDAC6 has emerged as an anti-ZIKV factor by targeting NS5.
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Affiliation(s)
- Silvia Pérez-Yanes
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
| | - Iria Lorenzo-Sánchez
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
| | - Romina Cabrera-Rodríguez
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
| | - Jonay García-Luis
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
| | - Rodrigo Trujillo-González
- Department of Análisis Matemático, Facultad de Ciencias, Universidad de La Laguna, 38296 La Laguna, Spain;
| | - Judith Estévez-Herrera
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
| | - Agustín Valenzuela-Fernández
- Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 La Laguna, Spain; (S.P.-Y.); (I.L.-S.); (R.C.-R.); (J.G.-L.)
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13
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Wang X, Tong W, Yang X, Zhai H, Qin W, Liu C, Zheng H, Yu H, Tong G, Zhang Z, Kong N, Shan T. RBM14 inhibits the replication of porcine epidemic diarrhea virus by recruiting p62 to degrade nucleocapsid protein through the activation of autophagy and interferon pathway. J Virol 2024; 98:e0018224. [PMID: 38411947 PMCID: PMC10949495 DOI: 10.1128/jvi.00182-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 02/05/2024] [Indexed: 02/28/2024] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) results in PED, which is an infectious intestinal disease with the representative features of diarrhea, vomiting, and dehydration. PEDV infects neonatal piglets, causing high mortality rates. Therefore, elucidating the interaction between the virus and host in preventing and controlling PEDV infection is of immense significance. We found a new antiviral function of the host protein, RNA-binding motif protein 14 (RBM14), which can inhibit PEDV replication via the activation of autophagy and interferon (IFN) signal pathways. We found that RBM14 can recruit cargo receptor p62 to degrade PEDV nucleocapsid (N) protein through the RBM14-p62-autophagosome pathway. Furthermore, RBM14 can also improve the antiviral ability of the hosts through interacting with mitochondrial antiviral signaling protein to induce IFN expression. These results highlight the novel mechanism underlying RBM14-induced viral restriction. This mechanism leads to the degradation of viral N protein via the autophagy pathway and upregulates IFN for inhibiting PEDV replication; thus, offering new ways for preventing and controlling PED.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) is a vital reason for diarrhea in neonatal piglets, which causes high morbidity and mortality rates. There is currently no effective vaccine or drug to treat and prevent infection with the PEDV. During virus infection, the host inhibits virus replication through various antiviral factors, and at the same time, the virus antagonizes the host's antiviral reaction through its own encoded protein, thus completing the process of virus replication. Our study has revealed that the expression of RNA-binding motif protein 14 (RBM14) was downregulated in PEDV infection. We found that RBM14 can recruit cargo receptor p62 to degrade PEDV N protein via the RBM14-p62-autophagosome pathway and interacted with mitochondrial antiviral signaling protein and TRAF3 to activate the interferon signal pathway, resulting in the inhibition of PEDV replication.
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Affiliation(s)
- Xiaoquan Wang
- Jiangsu University of Science and Technology, Zhenjiang, China
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Wu Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Xinyu Yang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Huanjie Zhai
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Wenzhen Qin
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Changlong Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Hao Zheng
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Hai Yu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Guangzhi Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Zhendong Zhang
- Jiangsu University of Science and Technology, Zhenjiang, China
| | - Ning Kong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
| | - Tongling Shan
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
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14
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Yang TH, Gao WC, Ma X, Liu Q, Pang PP, Zheng YT, Jia Y, Zheng CB. A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection. Viruses 2024; 16:365. [PMID: 38543730 PMCID: PMC10974792 DOI: 10.3390/v16030365] [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: 01/13/2024] [Revised: 02/20/2024] [Accepted: 02/25/2024] [Indexed: 05/23/2024] Open
Abstract
Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.
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Affiliation(s)
- Tie-Hua Yang
- School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming 650500, China; (T.-H.Y.); (P.-P.P.)
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; (X.M.); (Y.-T.Z.)
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Wen-Cong Gao
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China;
| | - Xin Ma
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; (X.M.); (Y.-T.Z.)
- College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China
| | - Qian Liu
- School of Pharmacy, Chongqing Medical University, Chongqing 400016, China;
| | - Pan-Pan Pang
- School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming 650500, China; (T.-H.Y.); (P.-P.P.)
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; (X.M.); (Y.-T.Z.)
| | - Yong-Tang Zheng
- Key Laboratory of Animal Models and Human Diseases Mechanisms of Chinese Academy of Sciences, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; (X.M.); (Y.-T.Z.)
- Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Yinnong Jia
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China;
| | - Chang-Bo Zheng
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China;
- College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China
- Yunnan Vaccine Laboratory, Kunming 650500, China
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15
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Li S, Xu B, Luo Y, Luo J, Huang S, Guo X. Autophagy and Apoptosis in Rabies Virus Replication. Cells 2024; 13:183. [PMID: 38247875 PMCID: PMC10814280 DOI: 10.3390/cells13020183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/28/2023] [Accepted: 01/16/2024] [Indexed: 01/23/2024] Open
Abstract
Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the Rhabdoviridae family and Lyssavirus genus, which is highly neurotropic and can infect almost all warm-blooded animals, including humans. Autophagy and apoptosis are two evolutionarily conserved and genetically regulated processes that maintain cellular and organismal homeostasis, respectively. Autophagy recycles unnecessary or dysfunctional intracellular organelles and molecules in a cell, whereas apoptosis eliminates damaged or unwanted cells in an organism. Studies have shown that RABV can induce both autophagy and apoptosis in target cells. To advance our understanding of pathogenesis of rabies, this paper reviews the molecular mechanisms of autophagy and apoptosis induced by RABV and the effects of the two cellular events on RABV replication.
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Affiliation(s)
- Saisai Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (S.L.); (Y.L.)
| | - Bowen Xu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, China;
| | - Yongwen Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (S.L.); (Y.L.)
| | - Jun Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (S.L.); (Y.L.)
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA;
- Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
| | - Xiaofeng Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; (S.L.); (Y.L.)
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16
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Sosa-Acosta P, Evaristo GPC, Evaristo JAM, Carneiro GRA, Quiñones-Vega M, Monnerat G, Melo A, Garcez PP, Nogueira FCS, Domont GB. Amniotic fluid metabolomics identifies impairment of glycerophospholipid and amino acid metabolism during congenital Zika syndrome development. Proteomics Clin Appl 2024; 18:e2300008. [PMID: 37329193 DOI: 10.1002/prca.202300008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/02/2023] [Accepted: 06/06/2023] [Indexed: 06/18/2023]
Abstract
PURPOSE Our main goal is to identify the alterations in the amniotic fluid (AF) metabolome in Zika virus (ZIKV)-infected patients and their relation to congenital Zika syndrome (CZS) progression. EXPERIMENTAL DESIGN We applied an untargeted metabolomics strategy to analyze seven AF of pregnant women: healthy women and ZIKV-infected women bearing non-microcephalic and microcephalic fetuses. RESULTS Infected patients were characterized by glycerophospholipid metabolism impairment, which is accentuated in microcephalic phenotypes. Glycerophospholipid decreased concentration in AF can be a consequence of intracellular transport of lipids to the placental or fetal tissues under development. The increased intracellular concentration of lipids can lead to mitochondrial dysfunction and neurodegeneration caused by lipid droplet accumulation. Furthermore, the dysregulation of amino acid metabolism was a molecular fingerprint of microcephalic phenotypes, specifically serine, and proline metabolisms. Both amino acid deficiencies were related to neurodegenerative disorders, intrauterine growth retardation, and placental abnormalities. CONCLUSIONS AND CLINICAL RELEVANCE This study enhances our understanding of the development of CZS pathology and sheds light on dysregulated pathways that could be relevant for future studies.
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Affiliation(s)
- Patricia Sosa-Acosta
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Geisa P C Evaristo
- Center of Applied Biomolecular Studies in Healthy, Osvaldo Cruz Foundation Unit of Rondônia, Porto Velho, Rondonia, Brazil
| | - Joseph A M Evaristo
- Center of Applied Biomolecular Studies in Healthy, Osvaldo Cruz Foundation Unit of Rondônia, Porto Velho, Rondonia, Brazil
| | - Gabriel Reis Alves Carneiro
- Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Mauricio Quiñones-Vega
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gustavo Monnerat
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory off Cardiac Electrophysiology Antônio Paes de Carvalho, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriana Melo
- Professor Amorim Neto Research Institute, Campina Grande, Paraíba, Brazil
| | - Patrícia P Garcez
- Institute of Biomedical Science, Federal University of Rio de Janeiro, RJ, Brazil
| | - Fábio C S Nogueira
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gilberto B Domont
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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17
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Sosa-Acosta P, Nogueira FCS, Domont GB. Proteomics and Metabolomics in Congenital Zika Syndrome: A Review of Molecular Insights and Biomarker Discovery. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1443:63-85. [PMID: 38409416 DOI: 10.1007/978-3-031-50624-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Zika virus (ZIKV) infection can be transmitted vertically, leading to the development of congenital Zika syndrome (CZS) in infected fetuses. During the early stages of gestation, the fetuses face an elevated risk of developing CZS. However, it is important to note that late-stage infections can also result in adverse outcomes. The differences between CZS and non-CZS phenotypes remain poorly understood. In this review, we provide a summary of the molecular mechanisms underlying ZIKV infection and placental and blood-brain barriers trespassing. Also, we have included molecular alterations that elucidate the progression of CZS by proteomics and metabolomics studies. Lastly, this review comprises investigations into body fluid samples, which have aided to identify potential biomarkers associated with CZS.
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Affiliation(s)
- Patricia Sosa-Acosta
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fábio C S Nogueira
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
- Laboratory of Proteomics (LabProt), LADETEC, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Gilberto B Domont
- Proteomics Unit, Department of Biochemistry, Institute of Chemistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
- Precision Medicine Research Center, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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18
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Wang C, Gao XY, Han M, Jiang MC, Shi XY, Pu CW, Du X. Perilipin2 inhibits the replication of hepatitis B virus deoxyribonucleic acid by regulating autophagy under high-fat conditions. World J Virol 2023; 12:296-308. [PMID: 38187502 PMCID: PMC10768386 DOI: 10.5501/wjv.v12.i5.296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/19/2023] [Accepted: 11/30/2023] [Indexed: 12/25/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is often associated with increased lipid deposition in hepatocytes. However, when combined with non-alcoholic fatty liver disease or hyperlipidemia, it tends to have a lower HBV deoxyribonucleic acid (DNA) load. The relationship between lipid metabolism and HBV DNA replication and its underlying mechanisms are not well understood. AIM To investigate the relationship between lipid metabolism and HBV DNA replication and its underlying mechanisms. METHODS 1603 HBsAg-seropositive patients were included in the study. We first explored the relationship between patients' lipid levels, hepatic steatosis, and HBV DNA load. Also, we constructed an HBV infection combined with a hepatic steatosis cell model in vitro by fatty acid stimulation of HepG2.2.15 cells to validate the effect of lipid metabolism on HBV DNA replication in vitro. By knocking down and overexpressing Plin2, we observed whether Plin2 regulates autophagy and HBV replication. By inhibiting both Plin2 and cellular autophagy under high lipid stimulation, we examined whether the Plin2-autophagy pathway regulates HBV replication. RESULTS The results revealed that serum triglyceride levels, high-density lipoprotein levels, and hepatic steatosis ratio were significantly lower in the HBV-DNA high load group. Logistic regression analysis indicated that hepatic steatosis and serum triglyceride levels were negatively correlated with HBV-DNA load. Stratified analysis by HBeAg showed significant negative correlations between HBV-DNA load and hepatic steatosis ratio in both HBeAg-positive and HBeAg-negative groups. An in vitro cell model was developed by stimulating HepG2.2.15 cells with palmitic acid and oleic acid to study the relationship between HBV-DNA load and lipid metabolism. The results of the in vitro experiments suggested that fatty acid treatment increased lipid droplet deposition and decreased the expression of cell supernatant HBsAg, HBeAg, and HBV DNA load. Western blot and polymerase chain reaction analysis showed that fatty acid stimulation significantly induced Plin2 protein expression and inhibited the expression of hepatocyte autophagy proteins. Inhibition of Plin2 protein expression under fatty acid stimulation reversed the reduction in HBsAg and HBeAg expression and HBV DNA load induced by fatty acid stimulation and the inhibition of cellular autophagy. Knocking down Plin2 and blocking autophagy with 3-methyladenine (3-MA) inhibited HBV DNA replication. CONCLUSION In conclusion, lipid metabolism is a significant factor affecting HBV load in patients with HBV infection. The in vitro experiments established that fatty acid stimulation inhibits HBV replication via the Plin2-autophagy pathway.
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Affiliation(s)
- Chuang Wang
- Graduate School, Graduate School of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Xiao-Yun Gao
- Department of Geriatric, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Mei Han
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Meng-Chun Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Xiao-Yi Shi
- Graduate School, Graduate School of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Chun-Wen Pu
- Dalian Public Health Clinical Center, Dalian Municipal Research Institute for Public Health, Dalian 116001, Liaoning Province, China
| | - Xuan Du
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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19
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Xu J, Yin P, Liu X, Hou X. Forsythoside A inhibits apoptosis and autophagy induced by infectious bronchitis virus through regulation of the PI3K/Akt/NF-κB pathway. Microbiol Spectr 2023; 11:e0192123. [PMID: 37971265 PMCID: PMC10715169 DOI: 10.1128/spectrum.01921-23] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 10/12/2023] [Indexed: 11/19/2023] Open
Abstract
IMPORTANCE Infectious bronchitis virus (IBV) is an acute and highly infectious viral disease that seriously endangered the development of the chicken industry. However, due to the limited effectiveness of commercial vaccines, there is an urgent need to develop safe and effective anti-IBV drugs. Forsythoside A (FTA) is a natural ingredient with wide pharmacological and biological activities, and it has been shown to have antiviral effects against IBV. However, the antiviral mechanism of FTA is still unclear. In this study, we demonstrated that FTA can inhibit cell apoptosis and autophagy induced by IBV infection by regulating the PI3K/AKT/NF-κB signaling pathway. This finding is important for exploring the role and mechanism of FTA in anti-IBV infection, indicating that FTA can be further studied as an anti-IBV drug.
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Affiliation(s)
- Jun Xu
- Department of Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Peng Yin
- Institute of Microbiology Chinese Academy of Sciences, Beijing, China
| | - Xuewei Liu
- Department of Veterinary Medicine, Beijing University of Agriculture, Beijing, China
| | - Xiaolin Hou
- Department of Veterinary Medicine, Beijing University of Agriculture, Beijing, China
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20
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Chaudhary Y, Jain J, Gaur SK, Tembhurne P, Chandrasekar S, Dhanavelu M, Sehrawat S, Kaul R. Nucleocapsid Protein (N) of Peste des petits ruminants Virus (PPRV) Interacts with Cellular Phosphatidylinositol-3-Kinase (PI3K) Complex-I and Induces Autophagy. Viruses 2023; 15:1805. [PMID: 37766213 PMCID: PMC10536322 DOI: 10.3390/v15091805] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 09/29/2023] Open
Abstract
Autophagy is an essential and highly conserved catabolic process in cells, which is important in the battle against intracellular pathogens. Viruses have evolved several ways to alter the host defense mechanisms. PPRV infection is known to modulate the components of a host cell's defense system, resulting in enhanced autophagy. In this study, we demonstrate that the N protein of PPRV interacts with the core components of the class III phosphatidylinositol-3-kinase (PI3K) complex-I and results in the induction of autophagy in the host cell over, thereby expressing this viral protein. Our data shows the interaction between PPRV-N protein and different core components of the autophagy pathway, i.e., VPS34, VPS15, BECN1 and ATG14L. The PPRV-N protein can specifically interact with VPS34 of the PI3K complex-I and colocalize with the proteins of PI3K complex-I in the same sub-cellular compartment, that is, in the cytoplasm. These interactions do not affect the intracellular localization of the different host proteins. The autophagy-related genes were transcriptionally modulated in PPRV-N-expressing cells. The expression of LC3B and SQSTM1/p62 was also modulated in PPRV-N-expressing cells, indicating the induction of autophagic activity. The formation of typical autophagosomes with double membranes was visualized by transmission electron microscopy in PPRV-N-expressing cells. Taken together, our findings provide evidence for the critical role of the N protein of the PPR virus in the induction of autophagy, which is likely to be mediated by PI3K complex-I of the host.
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Affiliation(s)
- Yash Chaudhary
- Department of Microbiology, University of Delhi, South Campus, New Delhi 110021, India; (Y.C.); (J.J.); (S.K.G.)
| | - Juhi Jain
- Department of Microbiology, University of Delhi, South Campus, New Delhi 110021, India; (Y.C.); (J.J.); (S.K.G.)
| | - Sharad Kumar Gaur
- Department of Microbiology, University of Delhi, South Campus, New Delhi 110021, India; (Y.C.); (J.J.); (S.K.G.)
| | - Prabhakar Tembhurne
- Department of Microbiology, Nagpur Veterinary College, Nagpur 440006, India;
| | - Shanmugam Chandrasekar
- Division of Virology, Indian Veterinary Research Institute, Mukteshwar, Nainital 263138, India; (S.C.); (M.D.)
| | - Muthuchelvan Dhanavelu
- Division of Virology, Indian Veterinary Research Institute, Mukteshwar, Nainital 263138, India; (S.C.); (M.D.)
| | - Sharvan Sehrawat
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali 140306, India;
| | - Rajeev Kaul
- Department of Microbiology, University of Delhi, South Campus, New Delhi 110021, India; (Y.C.); (J.J.); (S.K.G.)
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21
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Xie Y, Chi YL, Liu SQ, Zhu WY. BCX4430 inhibits the replication of rabies virus by suppressing mTOR-dependent autophagy invitro. Virology 2023; 585:21-31. [PMID: 37267717 DOI: 10.1016/j.virol.2023.05.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/04/2023]
Abstract
Rabies is a fatal neurological infectious disease caused by rabies virus (RABV). However, no effective anti-RABV drugs for treatment during the symptomatic phase are available. The novel adenosine nucleoside analog galidesivir (BCX4430) has broad-spectrum activity against a wide variety of highly pathogenic RNA viruses. In this study, we observed no apparent cytotoxicity of BCX4430 at the highest concentration of 250 μΜ, and which was displayed stronger antiviral activity against different virulent RABV in N2a or BHK-21 cells until 72 hpi. Meanwhile, BCX4430 showed greater anti-RABV activity than T-705 and anti-RABV activity similar to that of ribavirin in N2a cells. Furthermore, BCX4430 dose- and time-dependently inhibited RABV replication via mTOR-dependent autophagy inhibition in N2a cells with increased phospho-mTOR and phospho-SQSTM1 and decreased LC3-II levels. Taken together, these findings suggest that BCX4430 has potent anti-RABV activity in vitro and might provide a basis for the development of novel drug therapies against RABV.
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Affiliation(s)
- Yuan Xie
- Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, NHC Key Laboratory of Biosafety, Chinese Center for Disease Control and Prevention, Beijing, 102206, PR China
| | - Ying Lin Chi
- Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, NHC Key Laboratory of Biosafety, Chinese Center for Disease Control and Prevention, Beijing, 102206, PR China; School of Public Health, Baotou Medical College, Baotou, 014040, Inner Mongolia, PR China
| | - Shu Qing Liu
- Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, NHC Key Laboratory of Biosafety, Chinese Center for Disease Control and Prevention, Beijing, 102206, PR China.
| | - Wu Yang Zhu
- Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, NHC Key Laboratory of Biosafety, Chinese Center for Disease Control and Prevention, Beijing, 102206, PR China.
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22
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Ma X, Xia Q, Liu K, Wu Z, Li C, Xiao C, Dong N, Hameed M, Anwar MN, Li Z, Shao D, Li B, Qiu Y, Wei J, Ma Z. Palmitoylation at Residue C221 of Japanese Encephalitis Virus NS2A Protein Contributes to Viral Replication Efficiency and Virulence. J Virol 2023; 97:e0038223. [PMID: 37289075 PMCID: PMC10308905 DOI: 10.1128/jvi.00382-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/13/2023] [Indexed: 06/09/2023] Open
Abstract
Palmitoylation of viral proteins is crucial for host-virus interactions. In this study, we examined the palmitoylation of Japanese encephalitis virus (JEV) nonstructural protein 2A (NS2A) and observed that NS2A was palmitoylated at the C221 residue of NS2A. Blocking NS2A palmitoylation by introducing a cysteine-to-serine mutation at C221 (NS2A/C221S) impaired JEV replication in vitro and attenuated the virulence of JEV in mice. NS2A/C221S mutation had no effect on NS2A oligomerization and membrane-associated activities, but reduced protein stability and accelerated its degradation through the ubiquitin-proteasome pathway. These observations suggest that NS2A palmitoylation at C221 played a role in its protein stability, thereby contributing to JEV replication efficiency and virulence. Interestingly, the C221 residue undergoing palmitoylation was located at the C-terminal tail (amino acids 195 to 227) and is removed from the full-length NS2A following an internal cleavage processed by viral and/or host proteases during JEV infection. IMPORTANCE An internal cleavage site is present at the C terminus of JEV NS2A. Following occurrence of the internal cleavage, the C-terminal tail (amino acids 195 to 227) is removed from the full-length NS2A. Therefore, it was interesting to discover whether the C-terminal tail contributed to JEV infection. During analysis of viral palmitoylated protein, we observed that NS2A was palmitoylated at the C221 residue located at the C-terminal tail. Blocking NS2A palmitoylation by introducing a cysteine-to-serine mutation at C221 (NS2A/C221S) impaired JEV replication in vitro and attenuated JEV virulence in mice, suggesting that NS2A palmitoylation at C221 contributed to JEV replication and virulence. Based on these findings, we could infer that the C-terminal tail might play a role in the maintenance of JEV replication efficiency and virulence despite its removal from the full-length NS2A at a certain stage of JEV infection.
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Affiliation(s)
- Xiaochun Ma
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- College of Veterinary Medicine, Shandong Vocational Animal Science and Veterinary College, Weifang, People’s Republic of China
| | - Qiqi Xia
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Ke Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, People’s Republic of China
| | - Chenxi Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Changguang Xiao
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Nihua Dong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Muddassar Hameed
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Muhammad Naveed Anwar
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
- Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan
| | - Zongjie Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Donghua Shao
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Beibei Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Yafeng Qiu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Jianchao Wei
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
| | - Zhiyong Ma
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, People’s Republic of China
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23
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Shan T, Li LY, Yang JM, Cheng Y. Role and clinical implication of autophagy in COVID-19. Virol J 2023; 20:125. [PMID: 37328875 PMCID: PMC10276507 DOI: 10.1186/s12985-023-02069-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/10/2023] [Indexed: 06/18/2023] Open
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic constitutes a serious public health concern worldwide. Currently, more than 6 million deaths have occurred despite drastic containment measures, and this number is still increasing. Currently, no standard therapies for COVID-19 are available, which necessitates identifying effective preventive and therapeutic agents against COVID-19. However, developing new drugs and vaccines is a time-consuming process, and therefore, repurposing the existing drugs or redeveloping related targets seems to be the best strategy to develop effective therapeutics against COVID-19. Autophagy, a multistep lysosomal degradation pathway contributing to nutrient recycling and metabolic adaptation, is involved in the initiation and progression of numerous diseases as a part of an immune response. The key role of autophagy in antiviral immunity has been extensively studied. Moreover, autophagy can directly eliminate intracellular microorganisms by selective autophagy, that is, "xenophagy." However, viruses have acquired diverse strategies to exploit autophagy for their infection and replication. This review aims to trigger the interest in the field of autophagy as an antiviral target for viral pathogens (with an emphasis on COVID-19). We base this hypothesis on summarizing the classification and structure of coronaviruses as well as the process of SARS-CoV-2 infection and replication; providing the common understanding of autophagy; reviewing interactions between the mechanisms of viral entry/replication and the autophagy pathways; and discussing the current state of clinical trials of autophagy-modifying drugs in the treatment of SARS-CoV-2 infection. We anticipate that this review will contribute to the rapid development of therapeutics and vaccines against COVID-19.
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Affiliation(s)
- Tianjiao Shan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Lan-Ya Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, Department of Pharmacology, and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China.
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24
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Xing J, Hu C, Che S, Lan Y, Huang L, Liu L, Yin Y, Li H, Liao M, Qi W. USP1-Associated Factor 1 Modulates Japanese Encephalitis Virus Replication by Governing Autophagy and Interferon-Stimulated Genes. Microbiol Spectr 2023; 11:e0318622. [PMID: 36988464 PMCID: PMC10269463 DOI: 10.1128/spectrum.03186-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Japanese encephalitis virus (JEV) is a typical mosquito-borne flavivirus that can cause central nervous system diseases in humans and animals. Host factors attempt to limit virus replication when the viruses invade the host by using various strategies for replication. It is essential to clarify the host factors that affect the life cycle of JEV and explore its underlying mechanism. Here, we found that USP1-associated factor 1 (UAF1; also known as WD repeat-containing protein 48) modulated JEV replication. We found that JEV propagation significantly increased in UAF1-depleted Huh7 cells. Moreover, we found that knockdown of UAF1 activated cell autophagic flux in further functional analysis. Subsequently, we demonstrated that autophagy can be induced by JEV, which promotes viral replication by inhibiting interferon-stimulated gene (ISG) expression in Huh7 cells. The knockdown of UAF1 reduced ISG expression during JEV infection. To explore the possible roles of autophagy in UAF1-mediated inhibition of JEV propagation, we knocked out ATG7 to generate autophagy-deficient cells and found that depletion of UAF1 failed to promote JEV replication in ATG7 knockout cells. Moreover, in ATG7-deficient Huh7 cells, interference with UAF1 expression did not lead to the induction of autophagy. Taken together, these findings indicate that UAF1 is a critical regulator of autophagy and reveal a mechanism by which UAF1 knockdown activates autophagy to promote JEV replication. IMPORTANCE Host factors play an essential role in virus replication and pathogenesis. Although UAF1 is well known to form complexes with ubiquitin-specific proteases, little is known about the function of the UAF1 protein itself. In this study, we confirmed that UAF1 is involved in JEV replication. Notably, we discovered a novel function for UAF1 in regulating autophagy. Furthermore, we demonstrated that UAF1 modulated JEV replication through its autophagy regulation. This study is the first description of the novel function of UAF1 in regulating autophagy, and it clarifies the underlying mechanism of the antiviral effect of UAF1 against JEV. These results provide a new mechanistic insight into the functional annotation of UAF1 and provide a potential target for increasing virus production during vaccine production.
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Affiliation(s)
- Jinchao Xing
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
- Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Chen Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
- Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Siqi Che
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yixin Lan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Lihong Huang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Lele Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Youqin Yin
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
| | - Huanan Li
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
| | - Ming Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
- Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
| | - Wenbao Qi
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control, Guangzhou, China
- Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China
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25
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Viettri M, Caraballo G, Sanchez ME, Espejel-Nuñez A, Betanzos A, Ortiz-Navarrete V, Estrada-Gutierrez G, Nava P, Ludert JE. Comparative Infections of Zika, Dengue, and Yellow Fever Viruses in Human Cytotrophoblast-Derived Cells Suggest a Gating Role for the Cytotrophoblast in Zika Virus Placental Invasion. Microbiol Spectr 2023; 11:e0063023. [PMID: 37227282 PMCID: PMC10269719 DOI: 10.1128/spectrum.00630-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/01/2023] [Indexed: 05/26/2023] Open
Abstract
The Zika virus (ZIKV) is teratogenic and considered a TORCH pathogen (toxoplasmosis [Toxoplasma gondii], rubella, cytomegalovirus, herpes simplex virus [HSV], and other microorganisms capable of crossing the blood-placenta barrier). In contrast, the related flavivirus dengue virus (DENV) and the attenuated yellow fever virus vaccine strain (YFV-17D) are not. Understanding the mechanisms used by ZIKV to cross the placenta is necessary. In this work, parallel infections with ZIKV of African and Asian lineages, DENV, and YFV-17D were compared for kinetics and growth efficiency, activation of mTOR pathways, and cytokine secretion profile using cytotrophoblast-derived HTR8 cells and monocytic U937 cells differentiated to M2 macrophages. In HTR8 cells, ZIKV replication, especially the African strain, was significantly more efficient and faster than DENV or YFV-17D. In macrophages, ZIKV replication was also more efficient, although differences between strains were reduced. Greater activation of the mTORC1 and mTORC2 pathways in HTR8 cells infected with ZIKV than with DENV or YFV-17D was observed. HTR8 cells treated with mTOR inhibitors showed a 20-fold reduction in ZIKV yield, versus 5- and 3.5-fold reductions for DENV and YFV-17D, respectively. Finally, infection with ZIKV, but not DENV or YFV-17D, efficiently inhibited the interferon (IFN) and chemoattractant responses in both cell lines. These results suggest a gating role for the cytotrophoblast cells in favoring entry of ZIKV, but not DENV and YFV-17D, into the placental stroma. IMPORTANCE Zika virus acquisition during pregnancy is associated with severe fetal damage. The Zika virus is related to dengue virus and yellow fever virus, yet fetal damage has not been related to dengue or inadvertent vaccination for yellow fever during pregnancy. Mechanisms used by the Zika virus to cross the placenta need to be deciphered. By comparing parallel infections of Zika virus strains belonging to the African and Asian lineages, dengue virus, and the yellow fever vaccine virus strain YFV-17D in placenta-derived cytotrophoblast cells and differentiated macrophages, evidence was found that Zika virus infections, especially by the African strains, were more efficient in cytotrophoblast cells than dengue virus or yellow fever vaccine virus strain infections. Meanwhile, no significant differences were observed in macrophages. Robust activation of the mTOR signaling pathways and inhibition of the IFN and chemoattractant response appear to be related to the better growth capacity of the Zika viruses in the cytotrophoblast-derived cells.
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Affiliation(s)
- Mercedes Viettri
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Gerson Caraballo
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Maria Elena Sanchez
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | | | - Abigail Betanzos
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Vianney Ortiz-Navarrete
- Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | | | - Porfirio Nava
- Department of Biophysical Physiology and Neuroscience, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Juan E. Ludert
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
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26
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Stoyanova G, Jabeen S, Landazuri Vinueza J, Ghosh Roy S, Lockshin RA, Zakeri Z. Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication. Cell Commun Signal 2023; 21:114. [PMID: 37208782 DOI: 10.1186/s12964-022-01026-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 12/24/2022] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus. METHODS We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein. RESULTS Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells. CONCLUSIONS We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.
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Affiliation(s)
- Gloria Stoyanova
- Department of Biology, CUNY Queens College, Flushing, NY, 11367, USA
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Sidra Jabeen
- Department of Biology, CUNY Queens College, Flushing, NY, 11367, USA
- Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Joselyn Landazuri Vinueza
- Department of Biology, CUNY Queens College, Flushing, NY, 11367, USA
- Department of Microbiology, University of Washington, Seattle, WA, 98195, USA
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Sounak Ghosh Roy
- Department of Biology, CUNY Queens College, Flushing, NY, 11367, USA
- Henry Jackson Foundation for the Advancement of Military Medicine, Silver Spring, MD, 20910, USA
| | - Richard A Lockshin
- Department of Biological Sciences, St. John's University, Jamaica, NY, 11439, USA
| | - Zahra Zakeri
- Department of Biology, CUNY Queens College, Flushing, NY, 11367, USA.
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Zhang D, Ding Z, Xu X. Pathologic Mechanisms of the Newcastle Disease Virus. Viruses 2023; 15:v15040864. [PMID: 37112843 PMCID: PMC10143668 DOI: 10.3390/v15040864] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/18/2023] [Accepted: 03/26/2023] [Indexed: 03/30/2023] Open
Abstract
Newcastle disease (ND) has been a consistent risk factor to the poultry industry worldwide. Its pathogen, Newcastle disease virus (NDV), is also a promising antitumor treatment candidate. The pathogenic mechanism has intrigued the great curiosity of researchers, and advances in the last two decades have been summarized in this paper. The NDV’s pathogenic ability is highly related to the basic protein structure of the virus, which is described in the Introduction of this review. The overall clinical signs and recent findings pertaining to NDV-related lymph tissue damage are then described. Given the involvement of cytokines in the overall virulence of NDV, cytokines, particularly IL6 and IFN expressed during infection, are reviewed. On the other hand, the host also has its way of antagonizing the virus, which starts with the detection of the pathogen. Thus, advances in NDV’s physiological cell mechanism and the subsequent IFN response, autophagy, and apoptosis are summarized to provide a whole picture of the NDV infection process.
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Pordanjani PM, Bolhassani A, Milani A, Pouriayevali MH. Extracellular vesicles in vaccine development and therapeutic approaches for viral diseases. Process Biochem 2023. [DOI: 10.1016/j.procbio.2023.02.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
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29
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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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30
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Cao Y, Jing P, Yu L, Wu Z, Gao S, Bao W. miR-214-5p/C1QTNF1 axis enhances PCV2 replication through promoting autophagy by targeting AKT/mTOR signaling pathway. Virus Res 2023; 323:198990. [PMID: 36302471 PMCID: PMC10194317 DOI: 10.1016/j.virusres.2022.198990] [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: 07/31/2022] [Revised: 10/18/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
Abstract
Porcine circovirus type 2 (PCV2) is the causative agent of PCV2-associated disease, which causes a relevant economic impact on the global swine industry. Accumulating data have indicated host microRNAs play essential roles in numerous virus replication of pigs, while their roles in PCV2 replication remain unclear. Herein, we demonstrated that PCV2 infection downregulated the expression of miR-214-5p in PK15 cells, and miR-214-5p promoted PCV2 replication. C1q/tumor necrosis factor-related protein 1 (C1QTNF1) was then identified as a target gene of miR-214-5p, and C1QTNF1 suppressed PCV2 replication. Interestingly, miR-214-5p/C1QTNF1 axis negatively regulated AKT/mTOR signaling, and then enhanced PCV2 replication through promoting autophagy in PK15 cells. Collectively, our findings provide insight into the mechanism of PCV2 replication and highlight miR-214-5p and C1QTNF1 as potential novel targets for the treatment of PCV2 infection.
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Affiliation(s)
- Yue Cao
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Pengfei Jing
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Luchen Yu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Zhengchang Wu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China; College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
| | - Song Gao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
| | - Wenbin Bao
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
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31
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Liu B, Zhang Y, Ren H, Yao Q, Ba J, Luan J, Zhao P, Qin Z, Qi Z. mTOR signaling regulates Zika virus replication bidirectionally through autophagy and protein translation. J Med Virol 2023; 95:e28422. [PMID: 36546404 DOI: 10.1002/jmv.28422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/10/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Zika virus (ZIKV) reemerged in 2016 and attracted much more attention worldwide. To date, the limited knowledge of ZIKV interactions with host cells in the early stages of infection impedes the prevention of viral epidemics and the treatment of ZIKV disease. The mammalian target of rapamycin (mTOR) signaling pathway plays an essential role in the regulation of autophagy and protein synthesis during multiple viral infections. This study aimed to investigate the functional role of mTOR signaling in ZIKV replication in human umbilical vein endothelial cells. Immunoblotting demonstrated that ZIKV infection inhibited mTORC1 signaling, enhancing autophagy but obstructing protein translation. Drugs or siRNA for interfering with mTOR signaling molecules were utilized to demonstrate that AKT/TSC2/mTORC1 signaling was involved in ZIKV infection and that autophagy promoted ZIKV production, but viral protein expression was regulated by mTORC1 signaling. Moreover, confocal microscopy indicated a robust correlation between autophagy and viral RNA transcription. This study clarifies the dual functions of mTOR signaling during ZIKV infection and provides theoretical support for developing potential anti-ZIKV drugs based on mTOR signaling molecules and deeper insights to better understand the mechanism between ZIKV and host cells.
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Affiliation(s)
- Bin Liu
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China.,Naval Medical Center, Naval Medical University, Shanghai, China
| | - Yahui Zhang
- Department of Cardiology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Hao Ren
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Qiufeng Yao
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Jianbo Ba
- Naval Medical Center, Naval Medical University, Shanghai, China
| | - Jie Luan
- Naval Medical Center, Naval Medical University, Shanghai, China
| | - Ping Zhao
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Zhaoling Qin
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Zhongtian Qi
- Department of Microbiology, Naval Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
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32
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Leon KE, Khalid MM, Flynn RA, Fontaine KA, Nguyen TT, Kumar GR, Simoneau CR, Tomar S, Jimenez-Morales D, Dunlap M, Kaye J, Shah PS, Finkbeiner S, Krogan NJ, Bertozzi C, Carette JE, Ott M. Nuclear accumulation of host transcripts during Zika Virus Infection. PLoS Pathog 2023; 19:e1011070. [PMID: 36603024 PMCID: PMC9847913 DOI: 10.1371/journal.ppat.1011070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 01/18/2023] [Accepted: 12/17/2022] [Indexed: 01/06/2023] Open
Abstract
Zika virus (ZIKV) infects fetal neural progenitor cells (NPCs) causing severe neurodevelopmental disorders in utero. Multiple pathways involved in normal brain development are dysfunctional in infected NPCs but how ZIKV centrally reprograms these pathways remains unknown. Here we show that ZIKV infection disrupts subcellular partitioning of host transcripts critical for neurodevelopment in NPCs and functionally link this process to the up-frameshift protein 1 (UPF1). UPF1 is an RNA-binding protein known to regulate decay of cellular and viral RNAs and is less expressed in ZIKV-infected cells. Using infrared crosslinking immunoprecipitation and RNA sequencing (irCLIP-Seq), we show that a subset of mRNAs loses UPF1 binding in ZIKV-infected NPCs, consistent with UPF1's diminished expression. UPF1 target transcripts, however, are not altered in abundance but in subcellular localization, with mRNAs accumulating in the nucleus of infected or UPF1 knockdown cells. This leads to diminished protein expression of FREM2, a protein required for maintenance of NPC identity. Our results newly link UPF1 to the regulation of mRNA transport in NPCs, a process perturbed during ZIKV infection.
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Affiliation(s)
- Kristoffer E. Leon
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Department of Medicine, University of California, San Francisco, California, United States of America
- Medical Scientist Training Program, University of California, San Francisco, California, United States of America
- Biomedical Sciences Graduate Program, University of California, San Francisco, California, United States of America
| | - Mir M. Khalid
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - Ryan A. Flynn
- Stem Cell Program, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America
| | - Krystal A. Fontaine
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - Thong T. Nguyen
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - G. Renuka Kumar
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - Camille R. Simoneau
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Department of Medicine, University of California, San Francisco, California, United States of America
- Biomedical Sciences Graduate Program, University of California, San Francisco, California, United States of America
| | - Sakshi Tomar
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - David Jimenez-Morales
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, United States of America
| | - Mariah Dunlap
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - Julia Kaye
- J. David Gladstone Institutes, San Francisco, California, United States of America
| | - Priya S. Shah
- Departments of Chemical Engineering and Microbiology and Molecular Genetics, University of California, Davis, California, United States of America
| | - Steven Finkbeiner
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Center for Systems and Therapeutics and Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, California, United States of America
- Departments of Neurology and Physiology, University of California, San Francisco, California, United States of America
| | - Nevan J. Krogan
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, United States of America
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, United States of America
| | - Carolyn Bertozzi
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America
| | - Jan E. Carette
- Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America
| | - Melanie Ott
- J. David Gladstone Institutes, San Francisco, California, United States of America
- Department of Medicine, University of California, San Francisco, California, United States of America
- Chan Zuckerberg Biohub, San Francisco, California, United States of America
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Wu C, Zeng L, Yi W, Miao Y, Liu Y, Wang Q, Liu S, Peng G, Zheng Z, Xia J. Echovirus induces autophagy to promote viral replication via regulating mTOR/ULK1 signaling pathway. Front Immunol 2023; 14:1162208. [PMID: 37114059 PMCID: PMC10126370 DOI: 10.3389/fimmu.2023.1162208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/21/2023] [Indexed: 04/29/2023] Open
Abstract
Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection via regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection.
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Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Luzhi Zeng
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, China
| | - Wenfu Yi
- CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yuanjiu Miao
- CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yihan Liu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, China
| | - Qiming Wang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, China
| | - Shi Liu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Guoping Peng
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, China
| | - Zhenhua Zheng
- CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jianbo Xia,
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Shin S, Han D, Cho H, Kim E, Choi K. Non-cytopathic bovine viral diarrhoea virus 2 induces autophagy to enhance its replication. Vet Med Sci 2022; 9:405-416. [PMID: 36533845 PMCID: PMC9856993 DOI: 10.1002/vms3.1052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Bovine viral diarrhoea virus (BVDV) is an important viral pathogen that has an economic impact on the livestock industry worldwide. Autophagy is one of the earliest cell-autonomous defence mechanisms against microbial invasion, and many types of viruses can induce autophagy by infecting host cells. OBJECTIVES The aim of this study was to identify the role of autophagy in the pathogenesis of non-cytopathic (ncp) BVDV2 infection. METHODS Madin-Darby bovine kidney (MDBK) cells were treated with ncp BVDV2, rapamycin, or 3-methyladenine (MA) and ncp BVDV2 and then incubated at 37°C for 24 h. Cells were harvested, and the effects of autophagy were determined by transmission electron microscopy (TEM), confocal laser microscopy, western blotting and qRT-PCR. Apoptotic analysis was also performed using western blotting and flow cytometry. RESULTS In ncp BVDV2-infected MDBK cells, more autophagosomes were observed by TEM, and the number of microtubule-associated protein 1 light chain 3B (LC3B) with green fluorescent protein puncta was also increased. The ncp BVDV2-infected cells showed significantly enhanced conversion of LC3-I to LC3-II, as well as upregulation of autophagy-related proteins, including ATG5 and Beclin 1, and substantial degradation of p62/SQSTM1. These results are similar to those induced by rapamycin, an autophagy inducer. E2 protein expression, which is associated with viral replication, increased over time in ncp BVDV2-infected cells. Inhibition of autophagy by 3-MA in ncp BVDV2-infected MDBK cells downregulated the expressions of LC3-II, ATG5 and Beclin 1 and prevented the degradation of p62/SQSTM1. Moreover, the expressions of phosphorylated Akt and procaspase-3 were significantly increased in ncp BVDV2-infected cells. In addition, the mRNA level of protein kinase R (PKR) was significantly reduced in ncp BVDV2-infected cells. CONCLUSIONS Our results demonstrate that ncp BVDV2 infection induced autophagy in MDBK cells via anti-apoptosis and PKR suppression. Therefore, autophagy may play a role in establishing persistent infection caused by ncp BVDV.
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Affiliation(s)
- Seung‐Uk Shin
- Department of Animal Science and BiotechnologyCollege of Ecology and Environmental Science, Kyungpook National UniversitySangjuSouth Korea
| | - Du‐Gyeong Han
- Korea National Institute of HealthCheongjuChungcheongbuk‐doSouth Korea
| | - Hyung‐Chul Cho
- Department of Animal Science and BiotechnologyCollege of Ecology and Environmental Science, Kyungpook National UniversitySangjuSouth Korea
| | - Eun‐Mi Kim
- Department of Animal Science and BiotechnologyCollege of Ecology and Environmental Science, Kyungpook National UniversitySangjuSouth Korea
| | - Kyoung‐Seong Choi
- Department of Animal Science and BiotechnologyCollege of Ecology and Environmental Science, Kyungpook National UniversitySangjuSouth Korea
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Qin ZL, Yao QF, Zhao P, Ren H, Qi ZT. Zika virus infection triggers lipophagy by stimulating the AMPK-ULK1 signaling in human hepatoma cells. Front Cell Infect Microbiol 2022; 12:959029. [PMID: 36405969 PMCID: PMC9667116 DOI: 10.3389/fcimb.2022.959029] [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: 06/01/2022] [Accepted: 10/19/2022] [Indexed: 01/25/2023] Open
Abstract
Zika virus (ZIKV) is a globally transmitted mosquito-borne pathogen, and no effective treatment or vaccine is available yet. Lipophagy, a selective autophagy targeting lipid droplets (LDs), is an emerging subject in cellular lipid metabolism and energy homeostasis. However, the regulatory mechanism of lipid metabolism and the role of lipophagy in Zika virus infection remain largely unknown. Here, we demonstrated that ZIKV induced lipophagy by activating unc-51-like kinase 1 (ULK1) through activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) in Huh7 cells. Upon ZIKV infection, the average size and triglyceride content of LDs significantly decreased. Moreover, ZIKV infection significantly increased lysosomal biosynthesis and LD-lysosome fusion. The activities of AMPK at Thr-172 and ULK1 at Ser-556 were increased in ZIKV-infected cells and closely correlated with lipophagy induction. Silencing of AMPK expression inhibited ZIKV infection, autophagy induction, and LD-lysosome fusion and decreased the triglyceride content of the cells. The activities of mammalian target of rapamycin (mTOR) at Ser-2448 and ULK1 at Ser-757 were suppressed independently of AMPK during ZIKV infection. Therefore, ZIKV infection triggers AMPK-mediated lipophagy, and the LD-related lipid metabolism during ZIKV infection is mainly regulated via the AMPK-ULK1 signaling pathway.
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Zhang H, Huang J, Song Y, Liu X, Qian M, Huang P, Li Y, Zhao L, Wang H. Regulation of innate immune responses by rabies virus. Animal Model Exp Med 2022; 5:418-429. [PMID: 36138548 PMCID: PMC9610147 DOI: 10.1002/ame2.12273] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/31/2022] [Indexed: 11/10/2022] Open
Abstract
Rabies virus (RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people and public safety. It is well known that innate immunity is the critical first line of host defense against viral infection. It monitors the invading pathogens by recognizing the pathogen-associated molecular patterns and danger-associated molecular patterns through pattern-recognition receptors, leading to the production of type I interferons (IFNα/β), inflammatory cytokines, and chemokines, or the activation of autophagy or apoptosis to inhibit virus replication. In the case of RABV, the innate immune response is usually triggered when the skin or muscle is bitten or scratched. However, RABV has evolved many ways to escape or even hijack innate immune response to complete its own replication and eventually invades the central nervous system (CNS). Once RABV reaches the CNS, it cannot be wiped out by the immune system or any drugs. Therefore, a better understanding of the interplay between RABV and innate immunity is necessary to develop effective strategies to combat its infection. Here, we review the innate immune responses induced by RABV and illustrate the antagonism mechanisms of RABV to provide new insights for the control of rabies.
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Affiliation(s)
- Haili Zhang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Jingbo Huang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Yumeng Song
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Xingqi Liu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Meichen Qian
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Pei Huang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Yuanyuan Li
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
| | - Ling Zhao
- State Key Laboratory of Agricultural MicrobiologyHuazhong Agricultural UniversityWuhanChina
| | - Hualei Wang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of EducationInstitute of Zoonosis, and College of Veterinary Medicine, Jilin UniversityChangchunChina
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Jahangiri B, Saei AK, Obi PO, Asghari N, Lorzadeh S, Hekmatirad S, Rahmati M, Velayatipour F, Asghari MH, Saleem A, Moosavi MA. Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166484. [PMID: 35811032 DOI: 10.1016/j.bbadis.2022.166484] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/01/2022] [Accepted: 07/03/2022] [Indexed: 02/08/2023]
Abstract
Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated.
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Affiliation(s)
- Babak Jahangiri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Patience O Obi
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada
| | - Narjes Asghari
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Shirin Hekmatirad
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Velayatipour
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Mohammad Hosseni Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Ayesha Saleem
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada.
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran.
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Mungin JW, Chen X, Liu B. Interferon Epsilon Signaling Confers Attenuated Zika Replication in Human Vaginal Epithelial Cells. Pathogens 2022; 11:853. [PMID: 36014974 PMCID: PMC9415962 DOI: 10.3390/pathogens11080853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 07/18/2022] [Accepted: 07/27/2022] [Indexed: 02/07/2023] Open
Abstract
Zika virus (ZIKV) is an emerging flavivirus that causes congenital birth defects and neurological compilations in the human host. Although ZIKV is primarily transmitted through infected mosquitos, recent studies reveal sexual contact as a potential transmission route. In vagina-bearing individuals, the vaginal epithelium constitutes the first line of defense against viruses. However, it is unclear how ZIKV interacts with the vaginal epithelium to initiate ZIKV transmission. In this study, we demonstrate that exposing ZIKV to human vaginal epithelial cells (hVECs) resulted in de novo viral RNA replication, increased envelope viral protein production, and a steady, extracellular release of infectious viral particles. Interestingly, our data show that, despite an increase in viral load, the hVECs did not exhibit significant cytopathology in culture as other cell types typically do. Furthermore, our data reveal that the innate antiviral state of hVECs plays a crucial role in preventing viral cytopathology. For the first time, our data show that interferon epsilon inhibits ZIKV replication. Collectively, our results in this study provide a novel perspective on the viral susceptibility and replication dynamics during ZIKV infection in the human vaginal epithelium. These findings will be instrumental towards developing therapeutic agents aimed at eliminating the pathology caused by the virus.
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Affiliation(s)
| | | | - Bindong Liu
- Centers for AIDS Health Disparity Research, Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN 37208, USA; (J.W.M.J.); (X.C.)
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Li K, Ji Q, Jiang S, Zhang N. Advancement in the Development of Therapeutics Against Zika Virus Infection. Front Cell Infect Microbiol 2022; 12:946957. [PMID: 35880081 PMCID: PMC9307976 DOI: 10.3389/fcimb.2022.946957] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Zika virus (ZIKV), a re-emerging arbovirus, causes teratogenic effects on the fetus and normal nerve functions, resulting in harmful autoimmune responses, which call for the development of therapeutics against ZIKV infection. In this review, we introduce the pathogenesis of ZIKV infection and summarize the advancement in the development of therapeutics against ZIKV infection. It provides guidance for the development of effective therapeutics against ZIKV infection.
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Affiliation(s)
- Kangchen Li
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Qianting Ji
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology of Ministry of Education (MOE), National Health Commission (NHC) and Chinese Academy of Medical Sciences (CAMS), School of Basic Medical Sciences and Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
- *Correspondence: Shibo Jiang, ; Naru Zhang,
| | - Naru Zhang
- Department of Clinical Medicine, School of Medicine, Zhejiang University City College, Hangzhou, China
- *Correspondence: Shibo Jiang, ; Naru Zhang,
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Zheng J, Yue R, Yang R, Wu Q, Wu Y, Huang M, Chen X, Lin W, Huang J, Chen X, Jiang Y, Yang B, Liao Y. Visualization of Zika Virus Infection via a Light-Initiated Bio-Orthogonal Cycloaddition Labeling Strategy. Front Bioeng Biotechnol 2022; 10:940511. [PMID: 35875483 PMCID: PMC9305201 DOI: 10.3389/fbioe.2022.940511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Zika virus (ZIKV) is a re-emerging flavivirus that leads to devastating consequences for fetal development. It is crucial to visualize the pathogenicity activities of ZIKV ranging from infection pathways to immunity processes, but the accurate labeling of ZIKV remains challenging due to the lack of a reliable labeling technique. We introduce the photo-activated bio-orthogonal cycloaddition to construct a fluorogenic probe for the labeling and visualizing of ZIKV. Via a simple UV photoirradiation, the fluorogenic probes could be effectively labeled on the ZIKV. We demonstrated that it can be used for investigating the interaction between ZIKV and diverse cells and avoiding the autofluorescence phenomenon in traditional immunofluorescence assay. Thus, this bioorthogonal-enabled labeling strategy can serve as a promising approach to monitor and understand the interaction between the ZIKV and host cells.
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Affiliation(s)
- Judun Zheng
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Rui Yue
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Ronghua Yang
- Department of Burn and Plastic Surgery, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, China
| | - Qikang Wu
- Department of Clinical Laboratory, The First People’s Hospital of Foshan, Foshan, China
- Department of Burn Surgery & Department of Rheumatology, The First People’s Hospital of Foshan, Foshan, China
| | - Yunxia Wu
- Department of Clinical Laboratory, The First People’s Hospital of Foshan, Foshan, China
- Department of Burn Surgery & Department of Rheumatology, The First People’s Hospital of Foshan, Foshan, China
| | - Mingxing Huang
- Department of Infectious Disease, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Xu Chen
- Department of Infectious Disease, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Weiqiang Lin
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Jialin Huang
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Xiaodong Chen
- Department of Clinical Laboratory, The First People’s Hospital of Foshan, Foshan, China
- Department of Burn Surgery & Department of Rheumatology, The First People’s Hospital of Foshan, Foshan, China
- *Correspondence: Xiaodong Chen, ; Yideng Jiang, ; Bin Yang, ; Yuhui Liao,
| | - Yideng Jiang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
- *Correspondence: Xiaodong Chen, ; Yideng Jiang, ; Bin Yang, ; Yuhui Liao,
| | - Bin Yang
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Xiaodong Chen, ; Yideng Jiang, ; Bin Yang, ; Yuhui Liao,
| | - Yuhui Liao
- Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Disease, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
- *Correspondence: Xiaodong Chen, ; Yideng Jiang, ; Bin Yang, ; Yuhui Liao,
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Gao H, Xu L, Fan Z, Zhang X, Duan Z, Ren F. The Role of Autophagy in the Mother-to-Child Transmission of Pregnant Women With a High Level of HBV DNA. Front Cell Infect Microbiol 2022; 12:850747. [PMID: 35531331 PMCID: PMC9072787 DOI: 10.3389/fcimb.2022.850747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/22/2022] [Indexed: 12/01/2022] Open
Abstract
Background Mother-to-child transmission (MTCT) is the most common propagation mode of hepatitis B virus (HBV) transmission. Exploring the mechanisms of HBV MTCT is the key to protect infant from infection. In this study, we aim to clarify the important role of autophagy complicated in HBV MTCT. Methods A total of 169 placental samples were collected in this study, includes 144 HBV positive pregnant women and 25 normal pregnant women. In vitro, JEG-3 cells were treated with serum contained different HBV viral loads. Electron microscope was used to observed the number of autophagosome. RT-qPCR and western blotting were used to measure the expression level of autophagy relative genes and proteins respectively. Immunofluorescence was used to analyzed the expression of LC-3 of the frozen section of placental tissue. Results According to the number of autophagosomes and the expression level of autophagic genes mRNA and protein, autophagy was increased in HBV maternal placenta. Among the control, low viral load, medium viral load and high viral load groups, autophagy was significantly up-regulated with the increase of HBV viral loads. Also, autophagy was increased in the HBeAg positive pregnant women compared with their HBeAg negative counterparts. Also, autophagy in infant-infected group was up-regulated compared with infant-uninfected group. In vitro, choriocarcinoma JEG-3 cells were treated with the different HBV viral loads or different time incubation, the mRNA and protein of autophagy related genes was maximum expression in the medium viral load or treatment in a short period, but decreased in the high viral load treatment or with long-term HBV exposure. Conclusion Our study determines the high levels of viremia could be the cause of both increase autophagy activities and MTCT. Autophagy was significantly up-regulated in pregnant women with high viral load or HBeAg positive, which plays an important part in the HBV MTCT.
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Affiliation(s)
- Hong Gao
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
- Department of Gastroenterology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Ling Xu
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
| | - Zihao Fan
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
| | - Xiangying Zhang
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
| | - Feng Ren
- Beijing Youan Hospital/Beijing Institute of Hepatology, Capital Medical University, Beijing, China
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42
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Dual control of tick-borne encephalitis virus replication by autophagy in mouse macrophages. Virus Res 2022; 315:198778. [DOI: 10.1016/j.virusres.2022.198778] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/06/2022] [Accepted: 04/09/2022] [Indexed: 11/22/2022]
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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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44
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Zheng B, Gao Z, Liang L, Lu Y, Kong Y, Chen W, Lin K, Chen W, Mai J, Li Y, Ma C. Autophagy of hepatic stellate cell induced by Clonorchis sinensis. Mol Biol Rep 2021; 49:1895-1902. [PMID: 34825320 DOI: 10.1007/s11033-021-07001-9] [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: 09/28/2021] [Accepted: 11/19/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Clonorchis sinensis was a food-borne zoonotic parasite in the worldwide and also an important risk factor of hepatic fibrosis. Excretory/secretion products of C. sinensis (CsESPs) are involved in parasite-host interactions and contribute to the development of hepatic damage. The aim of the present study was to investigate whether CsESPs and CsTP (adult protein) could induce autophagy of hepatic stellate cells (HSCs) and further activate HSCs so as to participate in the pathogenesis of hepatic fibrosis. METHODS AND RESULTS The human hepatic stellate cell line LX-2 was stimulated by CsESPs and CsTP. CsESPs showed the effect on cell proliferation in methyl thiazolyl tetrazolium (MTT) assay while CsTP failed. Autophagosomes and autolysosomes were observed after the transmission mRFP-EGFP-LC3 plasmid into the LX-2 cells. CsESPs had more powerful to induce the accumulation of autophagosomes and autolysosomes to enhance autophagic flux compared with CsTP. Western-blotting analysis confirmed that the ratio of LC3-II/I in LX-2 cells was up-regulated after CsESPs treatment for 6 h, which further proved that CsESPs could induce autophagy in LX-2 cells. Meanwhile, q-PCR results showed that the mRNA levels of collagen I, collagen III and α-SMA decreased in LX-2 cells after treatment with autophagy inhibitor chloroquine, whereas they increased when combination with CsESPs. CONCLUSIONS These results suggested that CsESPs-induced autophagy might be involved in the activation of HSCs, and consequently participate in the pathogenesis of hepatic fibrosis caused by C. sinensis infection.
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Affiliation(s)
- Bao Zheng
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Zhiyan Gao
- Department of Morphology Experiment Center, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Liumei Liang
- KingMed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Yunyu Lu
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yongting Kong
- KingMed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Wanting Chen
- KingMed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Keying Lin
- KingMed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Wanqi Chen
- KingMed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Jingying Mai
- Department of Pathogen Biology & Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China
| | - Yanwen Li
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, 530021, People's Republic of China.
| | - Changling Ma
- Department of Pathogen Biology & Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China.
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Leiser OP, Hobbs EC, Sims AC, Korch GW, Taylor KL. Beyond the List: Bioagent-Agnostic Signatures Could Enable a More Flexible and Resilient Biodefense Posture Than an Approach Based on Priority Agent Lists Alone. Pathogens 2021; 10:1497. [PMID: 34832652 PMCID: PMC8623450 DOI: 10.3390/pathogens10111497] [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] [Received: 10/08/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 12/23/2022] Open
Abstract
As of 2021, the biothreat policy and research communities organize their efforts around lists of priority agents, which elides consideration of novel pathogens and biotoxins. For example, the Select Agents and Toxins list is composed of agents that historic biological warfare programs had weaponized or that have previously caused great harm during natural outbreaks. Similarly, lists of priority agents promulgated by the World Health Organization and the National Institute of Allergy and Infectious Diseases are composed of previously known pathogens and biotoxins. To fill this gap, we argue that the research/scientific and biodefense/biosecurity communities should categorize agents based on how they impact their hosts to augment current list-based paradigms. Specifically, we propose integrating the results of multi-omics studies to identify bioagent-agnostic signatures (BASs) of disease-namely, patterns of biomarkers that accurately and reproducibly predict the impacts of infection or intoxication without prior knowledge of the causative agent. Here, we highlight three pathways that investigators might exploit as sources of signals to construct BASs and their applicability to this framework. The research community will need to forge robust interdisciplinary teams to surmount substantial experimental, technical, and data analytic challenges that stand in the way of our long-term vision. However, if successful, our functionality-based BAS model could present a means to more effectively surveil for and treat known and novel agents alike.
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Affiliation(s)
- Owen P. Leiser
- Pacific Northwest National Laboratory, Seattle, WA 98109, USA; (O.P.L.); (E.C.H.)
| | - Errett C. Hobbs
- Pacific Northwest National Laboratory, Seattle, WA 98109, USA; (O.P.L.); (E.C.H.)
| | - Amy C. Sims
- Pacific Northwest National Laboratory, Richland, WA 99354, USA;
| | - George W. Korch
- Battelle National Biodefense Institute, LLC, Fort Detrick, MD 21072, USA;
| | - Karen L. Taylor
- Pacific Northwest National Laboratory, Seattle, WA 98109, USA; (O.P.L.); (E.C.H.)
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Transcriptomic Studies Suggest a Coincident Role for Apoptosis and Pyroptosis but Not for Autophagic Neuronal Death in TBEV-Infected Human Neuronal/Glial Cells. Viruses 2021; 13:v13112255. [PMID: 34835061 PMCID: PMC8620470 DOI: 10.3390/v13112255] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/01/2021] [Accepted: 11/04/2021] [Indexed: 12/19/2022] Open
Abstract
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.
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Genome-wide CRISPR screen identifies RACK1 as a critical host factor for flavivirus replication. J Virol 2021; 95:e0059621. [PMID: 34586867 PMCID: PMC8610583 DOI: 10.1128/jvi.00596-21] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus lifecycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles. Importance Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knock-out screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.
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Qiu J, Hu F, Shao T, Guo Y, Dai Z, Nie H, Olasunkanmi OI, Qi Y, Chen Y, Lin L, Zhao W, Zhong Z, Wang Y. Blocking of EGFR Signaling Is a Latent Strategy for the Improvement of Prognosis of HPV-Induced Cancer. Front Oncol 2021; 11:633794. [PMID: 34646755 PMCID: PMC8503613 DOI: 10.3389/fonc.2021.633794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 08/19/2021] [Indexed: 01/10/2023] Open
Abstract
Human papillomavirus (HPV) is a double-stranded DNA (dsDNA) virus, and its high-risk subtypes increase cancer risks. However, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms and the pathogenesis of HPV are crucial in the prevention of HPV-related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV-induced cancer common features. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV-positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV-negative (HPV-) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV- cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV- cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR-related pathways which in turn and consequently induce better prognosis.
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Affiliation(s)
- Jianfa Qiu
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Feifei Hu
- Department of Obstetrics, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tingting Shao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Yuqiang Guo
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Zongmao Dai
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Huanhuan Nie
- Department of Microbiology, Harbin Medical University, Harbin, China
| | | | - Yue Qi
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Yang Chen
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Lexun Lin
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Wenran Zhao
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Zhaohua Zhong
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Yan Wang
- Department of Microbiology, Harbin Medical University, Harbin, China
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McKinney JR, Seferovic MD, Major AM, Suter MA, Tardif SD, Patterson JL, Castro ECC, Aagaard KM. Placental Autophagy and Viral Replication Co-localize in Human and Non-human Primate Placentae Following Zika Virus Infection: Implications for Therapeutic Interventions. FRONTIERS IN VIROLOGY (LAUSANNE, SWITZERLAND) 2021; 1:720760. [PMID: 37431450 PMCID: PMC10331925 DOI: 10.3389/fviro.2021.720760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Background Multiple studies have shown both induction and inhibition of autophagy during Zika virus (ZIKV) infection. While some have proposed mechanisms by which autophagic dysregulation might facilitate ZIKV vertical transmission, there is a lack of in situ data in human and non-human primate models. This is an especially pertinent question as autophagy-inhibitors, such as hydroxychloroquine, have been proposed as potential therapeutic agents aimed at preventing vertical transmission of ZIKV and other RNA viruses. Objectives Given the paucity of pre-clinical data in support of either autophagic enhancement or inhibition of placental ZIKV viral infection, we sought to assess cellular, spatial, and temporal associations between placental ZIKV infection and measures of autophagy in human primary cell culture and congenital infection cases, as well as an experimental non-human primate (marmoset, Callithrix jacchus) model. Study Design Primary trophoblast cells were isolated from human placentae (n = 10) and infected in vitro with ZIKV. Autophagy-associated gene expression (ULK-1, BECN1, ATG5, ATG7, ATG12, ATG16L1, MAP1LC3A, MAP1LC3B, p62/SQSTM1) was then determined by TaqMan qPCR to determine fold-change with ZIKV-infection. In in vivo validation experiments, autophagy genes LC3B and p62/SQSTM1 were probed using in situ hybridization (ISH) in the placentae of human Congenital Zika Syndrome (CZS) cases (n = 3) and ZIKV-infected marmoset placenta (n = 1) and fetal tissue (n = 1). Infected and uninfected villi were compared for mean density and co-localization of autophagic protein markers. Results Studies of primary cultured human trophoblasts revealed decreased expression of autophagy genes ATG5 and p62/SQSTM1 in ZIKV-infected trophoblasts [ATG5 fold change (±SD) 0.734-fold (±0.722), p = 0.036; p62/SQSTM1 0.661-fold (±0.666), p = 0.029]. Histologic examination by ISH and immunohistochemistry confirmed spatial association of autophagy and ZIKV infection in human congenital infection cases, as well as marmoset placental and fetal tissue samples. When quantified by densitometric data, autophagic protein LC3B, and p62/SQSTM1 expression in marmoset placenta were significantly decreased in in situ ZIKV-infected villi compared to less-infected areas [LC3B mean 0.951 (95% CI, 0.930-0.971), p = 0.018; p62/SQSTM1 mean 0.863 (95% CI, 0.810-0.916), p = 0.024]. Conclusion In the current study, we observed that in the non-transformed human and non-human primate placenta, disruption (specifically down-regulation) of autophagy accompanies later ZIKV replication in vitro, in vivo, and in situ. The findings collectively suggest that dysregulated autophagy spatially and temporally accompanies placental ZIKV replication, providing the first in situ evidence in relevant primate pre-clinical and clinical models for the importance of timing of human therapeutic strategies aimed at agonizing/antagonizing autophagy. These studies have likely further implications for other congenitally transmitted viruses, particularly the RNA viruses, given the ubiquitous nature of autophagic disruption and dysregulation in host responses to viral infection during pregnancy.
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Affiliation(s)
- Jennifer R. McKinney
- Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
| | - Maxim D. Seferovic
- Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
| | - Angela M. Major
- Pathology and Laboratory Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
| | - Melissa A. Suter
- Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
| | - Suzette D. Tardif
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Jean L. Patterson
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Eumenia C. C. Castro
- Pathology and Laboratory Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
| | - Kjersti M. Aagaard
- Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
- Pathology and Laboratory Medicine, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
- Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
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50
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Wang C, Li Y, Li Y, Du L, Zhang J, Li N, Hu X, Zhang W, Xie N, Ming L. FAM134B-Mediated ER-Phagy in Mg 2+-Free Solution-Induced Mitochondrial Calcium Homeostasis and Cell Death in Epileptic Hippocampal Neurons. Neurochem Res 2021; 46:2485-2494. [PMID: 34212292 DOI: 10.1007/s11064-021-03389-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022]
Abstract
Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) regulate calcium (Ca2+) homeostasis via Ca2+ transport-related proteins such as inositol-1,4,5-triphosphate receptor (IP3R). FAM134B-mediated ER-phagy plays an important role in ER homeostasis. However, it remains unknown whether FAM134B-mediated ER-phagy affects mitochondrial Ca2+ homeostasis and cell death through MAMs. In this study, we demonstrated that colocalization degree of FAM134B with LC3 and the LC3-II/LC3-I ratio were elevated in the hippocampal neuronal culture (HNC) model of acquired epilepsy (AE), which indicate an increased level of autophagy. In this model, FAM134B overexpression enhanced ER-phagy, while FAM134B downregulation had the opposite effect. Additionally, FAM134B overexpression significantly reversed the increases in IP3R expression and mitochondrial Ca2+ concentration and the decrease in the ER Ca2+ concentration in this model. FAM134B overexpression also ameliorated the AE-induced ultrastructural damage in neuronal mitochondria, decrease in mitochondrial membrane potential (mMP), cytochrome c (CytC) release and caspase-3 activation, while FAM134B downregulation induced the opposite effects. Altogether, our data indicate that FAM134B-mediated ER-phagy can attenuate AE-induced neuronal apoptosis, possibly by modulating the IP3R in MAMs to alter Ca2+ exchange between ER and mitochondria and thus inhibit mitochondrial structural damage, a decrease in mMP, release of CytC and mitochondrial apoptosis.
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Affiliation(s)
- Cui Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yujuan Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yingjiao Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Liyuan Du
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jingyu Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Nan Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiaomei Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenjing Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Nanchang Xie
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Liang Ming
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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