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1
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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [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: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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2
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Kushwaha S, Goel A, Singh AV. Serum microRNA Biomarker Expression in HIV and TB: A Concise Overview. Infect Disord Drug Targets 2025; 25:e18715265305638. [PMID: 39506419 DOI: 10.2174/0118715265305638240930054842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 11/08/2024]
Abstract
Non-coding RNAs (ncRNAs), specifically MicroRNAs or miRNAs, are now understood to be essential regulators in the complex field of gene expression. By selectively binding to certain mRNA targets, these tiny RNA molecules control the expression of genes, leading to mRNA degradation or translational repression. The discovery of miRNAs has significantly advanced biomedical research, particularly in elucidating the molecular mechanisms underlying various diseases and exploring innovative therapeutic approaches. Recent progress in miRNA research has provided insights into their biogenesis, functional roles, and potential clinical applications. Despite the absence of established methodologies for clinical implementation, miRNAs show great promise as diagnostic and therapeutic agents for a wide array of diseases. Their distinctive attributes, such as high specificity, sensitivity, and accessibility, position them as ideal candidates for biomarker development and targeted therapy. Achieving a comprehensive understanding of miRNA biology and functionality is crucial to fully harnessing their potential in medicine. Ongoing research efforts aim to unravel the intricate mechanisms of miRNA-mediated gene regulation and to develop novel approaches for utilizing miRNAs in disease diagnosis, prognosis, and treatment. This review provides a comprehensive analysis of current knowledge on miRNAs, focusing on their biogenesis, regulatory mechanisms, and potential clinical applications. By synthesizing existing evidence and highlighting key research findings, this review aims to inspire further exploration into the diverse roles of miRNAs in health and disease. Ultimately, this endeavour could result in the development of innovative miRNA-based diagnostic and therapeutic strategies.
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Affiliation(s)
- Shweta Kushwaha
- Department of Microbiology and Molecular Biology, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282004, Uttar Pradesh, India
- Department of Biotechnology, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Anjana Goel
- Department of Biotechnology, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Ajay Vir Singh
- Department of Microbiology and Molecular Biology, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, 282004, Uttar Pradesh, India
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3
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Oh JJ, Jaggi U, Tormanen K, Wang S, Hirose S, Ghiasi H. The anti-apoptotic function of HSV-1 LAT in neuronal cell cultures but not its function during reactivation correlates with expression of two small non-coding RNAs, sncRNA1&2. PLoS Pathog 2024; 20:e1012307. [PMID: 38857310 PMCID: PMC11192303 DOI: 10.1371/journal.ppat.1012307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/21/2024] [Accepted: 05/30/2024] [Indexed: 06/12/2024] Open
Abstract
Multiple functions are associated with HSV-1 latency associated transcript (LAT), including establishment of latency, virus reactivation, and antiapoptotic activity. LAT encodes two sncRNAs that are not miRNAs and previously it was shown that they have antiapoptotic activity in vitro. To determine if we can separate the antiapoptotic function of LAT from its latency-reactivation function, we deleted sncRNA1 and sncRNA2 sequences in HSV-1 strain McKrae, creating ΔsncRNA1&2 recombinant virus. Deletion of the sncRNA1&2 in ΔsncRNA1&2 virus was confirmed by complete sequencing of ΔsncRNA1&2 virus and its parental virus. Replication of ΔsncRNA1&2 virus in tissue culture or in the eyes of WT infected mice was similar to that of HSV-1 strain McKrae (LAT-plus) and dLAT2903 (LAT-minus) viruses. The levels of gB DNA in trigeminal ganglia (TG) of mice latently infected with ΔsncRNA1&2 virus was intermediate to that of dLAT2903 and McKrae infected mice, while levels of LAT in TG of latently infected ΔsncRNA1&2 mice was significantly higher than in McKrae infected mice. Similarly, the levels of LAT expression in Neuro-2A cells infected with ΔsncRNA1&2 virus was significantly higher than in McKrae infected cells. Reactivation in TG of ΔsncRNA1&2 infected mice was similar to that of McKrae and time of reactivation in both groups were significantly faster than dLAT2903 infected mice. However, levels of apoptosis in Neuro-2A cells infected with ΔsncRNA1&2 virus was similar to that of dLAT2903 and significantly higher than that of McKrae infected cells. Our results suggest that the antiapoptotic function of LAT resides within the two sncRNAs, which works independently of its latency-reactivation function and it has suppressive effect on LAT expression in vivo and in vitro.
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Affiliation(s)
- Jay J. Oh
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
| | - Ujjaldeep Jaggi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
| | - Kati Tormanen
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
| | - Shaohui Wang
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
| | - Satoshi Hirose
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
| | - Homayon Ghiasi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, United States of America
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4
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Naqvi RA, Valverde A, Yadavalli T, Bobat FI, Capistrano KJ, Shukla D, Naqvi AR. Viral MicroRNAs in Herpes Simplex Virus 1 Pathobiology. Curr Pharm Des 2024; 30:649-665. [PMID: 38347772 DOI: 10.2174/0113816128286469240129100313] [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: 10/10/2023] [Accepted: 01/17/2024] [Indexed: 06/01/2024]
Abstract
Simplexvirus humanalpha1 (Herpes simplex virus type 1 [HSV-1]) infects millions of people globally, manifesting as vesiculo-ulcerative lesions of the oral or genital mucosa. After primary infection, the virus establishes latency in the peripheral neurons and reactivates sporadically in response to various environmental and genetic factors. A unique feature of herpesviruses is their ability to encode tiny noncoding RNAs called microRNA (miRNAs). Simplexvirus humanalpha1 encodes eighteen miRNA precursors that generate twentyseven different mature miRNA sequences. Unique Simplexvirus humanalpha1 miRNAs repertoire is expressed in lytic and latent stages and exhibits expressional disparity in various cell types and model systems, suggesting their key pathological functions. This review will focus on elucidating the mechanisms underlying the regulation of host-virus interaction by HSV-1 encoded viral miRNAs. Numerous studies have demonstrated sequence- specific targeting of both viral and host transcripts by Simplexvirus humanalpha1 miRNAs. While these noncoding RNAs predominantly target viral genes involved in viral life cycle switch, they regulate host genes involved in antiviral immunity, thereby facilitating viral evasion and lifelong viral persistence inside the host. Expression of Simplexvirus humanalpha1 miRNAs has been associated with disease progression and resolution. Systemic circulation and stability of viral miRNAs compared to viral mRNAs can be harnessed to utilize their potential as diagnostic and prognostic markers. Moreover, functional inhibition of these enigmatic molecules may allow us to devise strategies that have therapeutic significance to contain Simplexvirus humanalpha1 infection.
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Affiliation(s)
- Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Tejabhiram Yadavalli
- Department of Ophthalmology and Visual Sciences, Medical Center, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Fatima Ismail Bobat
- Department of Ophthalmology and Visual Sciences, Medical Center, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Kristelle J Capistrano
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Deepak Shukla
- Department of Ophthalmology and Visual Sciences, Medical Center, University of Illinois Chicago, Chicago, Illinois 60607, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60607, USA
| | - Afsar R Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, Illinois 60607, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois 60607, USA
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5
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Gouzouasis V, Tastsoglou S, Giannakakis A, Hatzigeorgiou AG. Virus-Derived Small RNAs and microRNAs in Health and Disease. Annu Rev Biomed Data Sci 2023; 6:275-298. [PMID: 37159873 DOI: 10.1146/annurev-biodatasci-122220-111429] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that can regulate all steps of gene expression (induction, transcription, and translation). Several virus families, primarily double-stranded DNA viruses, encode small RNAs (sRNAs), including miRNAs. These virus-derived miRNAs (v-miRNAs) help the virus evade the host's innate and adaptive immune system and maintain an environment of chronic latent infection. In this review, the functions of the sRNA-mediated virus-host interactions are highlighted, delineating their implication in chronic stress, inflammation, immunopathology, and disease. We provide insights into the latest viral RNA-based research-in silico approaches for functional characterization of v-miRNAs and other RNA types. The latest research can assist toward the identification of therapeutic targets to combat viral infections.
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Affiliation(s)
- Vasileios Gouzouasis
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece;
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece
| | - Spyros Tastsoglou
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece;
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece
| | - Antonis Giannakakis
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, Athens, Greece
| | - Artemis G Hatzigeorgiou
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece;
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece
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6
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Pös O, Styk J, Buglyó G, Zeman M, Lukyova L, Bernatova K, Hrckova Turnova E, Rendek T, Csók Á, Repiska V, Nagy B, Szemes T. Cross-Kingdom Interaction of miRNAs and Gut Microbiota with Non-Invasive Diagnostic and Therapeutic Implications in Colorectal Cancer. Int J Mol Sci 2023; 24:10520. [PMID: 37445698 DOI: 10.3390/ijms241310520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Colorectal cancer (CRC) has one of the highest incidences among all types of malignant diseases, affecting millions of people worldwide. It shows slow progression, making it preventable. However, this is not the case due to shortcomings in its diagnostic and management procedure and a lack of effective non-invasive biomarkers for screening. Here, we discuss CRC-associated microRNAs (miRNAs) and gut microbial species with potential as CRC diagnostic and therapy biomarkers. We provide rich evidence of cross-kingdom miRNA-mediated interactions between the host and gut microbiome. miRNAs have emerged with the ability to shape the composition and dynamics of gut microbiota. Intestinal microbes can uptake miRNAs, which in turn influence microbial growth and provide the ability to regulate the abundance of various microbial species. In the context of CRC, targeting miRNAs could aid in manipulating the balance of the microbiota. Our findings suggest the need for correlation analysis between the composition of the gut microbiome and the miRNA expression profile.
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Affiliation(s)
- Ondrej Pös
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Jakub Styk
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Michal Zeman
- Comenius University Science Park, 841 04 Bratislava, Slovakia
| | - Lydia Lukyova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Kamila Bernatova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
| | - Evelina Hrckova Turnova
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Slovgen Ltd., 841 04 Bratislava, Slovakia
| | - Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Ádám Csók
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
- Medirex Group Academy, n.p.o., 949 05 Nitra, Slovakia
| | - Bálint Nagy
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Tomas Szemes
- Comenius University Science Park, 841 04 Bratislava, Slovakia
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
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7
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Duan Y, Sun L, Li Q. Herpes Simplex Virus 1 MicroRNAs: An Update. Intervirology 2023; 66:97-110. [PMID: 37285807 PMCID: PMC10389796 DOI: 10.1159/000531348] [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: 05/23/2022] [Accepted: 05/24/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Herpes simplex virus 1 (HSV-1), an important human pathogen, is capable of latent infection in neurons and productive (lytic) infection in other tissue cells. Once infected with HSV-1, the immune system of the organism cannot eliminate the virus and carries it lifelong. HSV-1 possesses approximately 150 kb of double-stranded linear genomic DNA and can encode at least 70 proteins and 37 mature microRNAs (miRNAs) derived from 18 precursor miRNAs (pre-miRNAs). SUMMARY These HSV-1-encoded miRNAs are widely involved in multiple processes in the life cycle of the virus and the host cell, including viral latent and lytic infection, as well as host cell immune signaling, proliferation, and apoptosis. KEY MESSAGE In this review, we focused primarily on recent advances in HSV-1-encoded miRNA expression, function, and mechanism, which may provide new research ideas and feasible research methods systemically and comprehensively.
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Affiliation(s)
- Yongzhong Duan
- Academy of Biomedical Engineering, Kunming Medical University, Kunming, China,
| | - Le Sun
- Basic Medical College, Kunming Medical University, Kunming, China
| | - Qihan Li
- Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
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8
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miRNAs in Herpesvirus Infection: Powerful Regulators in Small Packages. Viruses 2023; 15:v15020429. [PMID: 36851643 PMCID: PMC9965283 DOI: 10.3390/v15020429] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
microRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host-pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions.
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9
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Yaghobi R, Afshari A, Roozbeh J. Host and viral
RNA
dysregulation during
BK
polyomavirus
infection in kidney transplant recipients. WIRES RNA 2022:e1769. [DOI: 10.1002/wrna.1769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/12/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Ramin Yaghobi
- Shiraz Transplant Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Afsoon Afshari
- Shiraz Nephro‐Urology Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Jamshid Roozbeh
- Shiraz Nephro‐Urology Research Center Shiraz University of Medical Sciences Shiraz Iran
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10
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Hemmat N, Asadzadeh H, Asadzadeh Z, Shadbad MA, Baradaran B. The Analysis of Herpes Simplex Virus Type 1 (HSV-1)-Encoded MicroRNAs Targets: A Likely Relationship of Alzheimer's Disease and HSV-1 Infection. Cell Mol Neurobiol 2022; 42:2849-2861. [PMID: 34661780 PMCID: PMC11421598 DOI: 10.1007/s10571-021-01154-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/01/2021] [Indexed: 10/20/2022]
Abstract
Alzheimer's disease (AD), the most frequently diagnosed dementia, is a senile neurodegenerative disorder characterized by amnesia and cognitive dysfunction. Unfortunately, there are still no successful strategies to prevent AD progression. Thus, the vast majority of research focuses on recognizing risk factors for developing and progressing this disease. Human spirochetes, fungi, Borrelia burgdorferi, Chlamydophila pneumoniae, Helicobacter pylori, and human herpes simplex virus type 1 (HSV-1) have all been implicated in the development and progression of AD. Identifying microRNAs (miRs) encoded by DNA viruses has indicated that viruses can be evolved to exploit RNA silencing to regulate host and viral genes. Similar to host miR, v-miR can interact with the 3' untranslated region (UTR) of the target mRNA to regulate gene expression. Although HSV-1 can also encode various miRs, their significance in the development and progression of AD is still unclear. In the present study, utilizing the bioinformatics approach (R software and related packages), we analyzed the differentially expressed genes (DEGs) in AD samples (grey matter) of GSE37263 dataset obtained from the NCBI Gene Expression Omnibus (GEO). Then, the sequences of HSV-1-encoded-miRs were retrieved from miRbase, and their targets were predicted by miRDB. Afterward, the common genes between downregulated DEGs in AD and targets of HSV-1-encoded miRs were identified to shed new light on the relationship between HSV-1 infection and AD development. Our results have indicated that HSV-1-encoded-miRs can target the downregulated DEGs in AD, and these aberrant interactions can offer valuable diagnostic/prognostic biomarkers for affected patients.
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Affiliation(s)
- Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haniyeh Asadzadeh
- Department of Psychology, Ardabil Branch of Islamic Azad University, Ardabil, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Abdoli Shadbad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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11
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The Virus-Induced Upregulation of the miR-183/96/182 Cluster and the FoxO Family Protein Members Are Not Required for Efficient Replication of HSV-1. Viruses 2022; 14:v14081661. [PMID: 36016282 PMCID: PMC9414244 DOI: 10.3390/v14081661] [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: 05/24/2022] [Revised: 07/25/2022] [Accepted: 07/25/2022] [Indexed: 12/07/2022] Open
Abstract
Herpes simplex virus 1 (HSV-1) expresses a large number of miRNAs, and their function is still not completely understood. In addition, HSV-1 has been found to deregulate host miRNAs, which adds to the complexity of the regulation of efficient virus replication. In this study, we comprehensively addressed the deregulation of host miRNAs by massive-parallel sequencing. We found that only miRNAs expressed from a single cluster, miR-183/96/182, are reproducibly deregulated during productive infection. These miRNAs are predicted to regulate a great number of potential targets involved in different cellular processes and have only 33 shared targets. Among these, members of the FoxO family of proteins were identified as potential targets for all three miRNAs. However, our study shows that the upregulated miRNAs do not affect the expression of FoxO proteins, moreover, these proteins were upregulated in HSV-1 infection. Furthermore, we show that the individual FoxO proteins are not required for efficient HSV-1 replication. Taken together, our results indicate a complex and redundant response of infected cells to the virus infection that is efficiently inhibited by the virus.
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12
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Small Noncoding RNA (sncRNA1) within the Latency-Associated Transcript Modulates Herpes Simplex Virus 1 Virulence and the Host Immune Response during Acute but Not Latent Infection. J Virol 2022; 96:e0005422. [DOI: 10.1128/jvi.00054-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
HSV-1 latency-associated transcript (LAT) plays a major role in establishing latency and reactivation; however, the mechanism by which LAT controls these processes is largely unknown. In this study, we sought to establish the role of the small noncoding RNA1 (sncRNA1) encoded within LAT during HSV-1 ocular infection. Our results suggest that sncRNA1 has a protective role during acute ocular infection by modulating the innate immune response to infection.
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13
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Tormanen K, Wang S, Matundan HH, Yu J, Jaggi U, Ghiasi H. Herpes Simplex Virus 1 Small Noncoding RNAs 1 and 2 Activate the Herpesvirus Entry Mediator Promoter. J Virol 2022; 96:e0198521. [PMID: 34851143 PMCID: PMC8826802 DOI: 10.1128/jvi.01985-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 11/20/2022] Open
Abstract
Herpes simplex virus 1 (HSV-1) latency-associated transcript (LAT) plays a significant role in efficient establishment of latency and reactivation. LAT has antiapoptotic activity and downregulates expression of components of the type I interferon pathway. LAT also specifically activates expression of the herpesvirus entry mediator (HVEM), one of seven known receptors used by HSV-1 for cell entry that is crucial for latency and reactivation. However, the mechanism by which LAT regulates HVEM expression is not known. LAT has two small noncoding RNAs (sncRNAs) that are not microRNAs (miRNAs), within its 1.5-kb stable transcript, which also have antiapoptotic activity. These sncRNAs may encode short peptides, but experimental evidence is lacking. Here, we demonstrate that these two sncRNAs control HVEM expression by activating its promoter. Both sncRNAs are required for wild-type (WT) levels of activation of HVEM, and sncRNA1 is more important in HVEM activation than sncRNA2. Disruption of a putative start codon in sncRNA1 and sncRNA2 sequences reduced HVEM promoter activity, suggesting that sncRNAs encode a protein. However, we did not detect peptide binding using two chromatin immunoprecipitation (ChIP) approaches, and a web-based algorithm predicts low probability that the putative peptides bind to DNA. In addition, computational modeling predicts that sncRNA molecules bind with high affinity to the HVEM promoter, and deletion of these binding sites to sncRNA1, sncRNA2, or both reduced HVEM promoter activity. Together, our data suggest that sncRNAs exert their function as RNA molecules, not as proteins, and we provide a model for the predicted binding affinities and binding sites of sncRNA1 and sncRNA2 in the HVEM promoter. IMPORTANCE HSV-1 causes recurrent ocular infections, which is the leading cause of corneal scarring and blindness. Corneal scarring is caused by the host immune response to repeated reactivation events. LAT functions by regulating latency and reactivation, in part by inhibiting apoptosis and activating HVEM expression. However, the mechanism used by LAT to control HVEM expression is unclear. Here, we demonstrate that two sncRNAs within the 1.5-kb LAT transcript activate HVEM expression by binding to two regions of its promoter. Interfering with these interactions may reduce latency and thereby eye disease associated with reactivation.
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Affiliation(s)
- Kati Tormanen
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
| | - Shaohui Wang
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
| | - Harry H. Matundan
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
| | - Jack Yu
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
| | - Ujjaldeep Jaggi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
| | - Homayon Ghiasi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, CSMC–SSB3, Los Angeles, California, USA
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14
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Paul S, Saikia M, Chakraborty S. Identification of novel microRNAs in Rous sarcoma Virus (RSV) and their target sites in tumor suppressor genes of chicken. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 96:105139. [PMID: 34798320 DOI: 10.1016/j.meegid.2021.105139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 11/09/2021] [Indexed: 06/13/2023]
Abstract
A small non-coding, evolutionarily conserved regulatory RNA molecule known as microRNA (miRNA) regulates various cellular activities and pathways. MicroRNAs remain evolutionarily conserved in different species of same taxa. They are present in all organisms including viruses. Viral miRNAs are small, less conserved and less stable and have higher negative minimal folding free energy than miRNAs of different organisms. The size of viral precursor miRNA is approximately 60-119 nucleotides in length. The structure of the mature miRNA sequences is predicted by using higher negative MFE (ΔG) value. Rous sarcoma Virus (RSV), named after its inventor Peyton Rous, has been known for causing tumors in the chicken for which it is known as an oncogenic retrovirus. Using specific criteria we have predicted 5 potential miRNAs in RSV which targeted 8 tumor suppressor genes in Gallus gallus. This study aims to predict the potential miRNAs, secondary structures and their targets for better understanding of the regulatory network of Rous sarcoma virus miRNA in forming sarcoma.
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Affiliation(s)
- Sunanda Paul
- Department of Biotechnology, Assam University, Silchar 788011, Assam, India
| | - Momi Saikia
- Department of Biotechnology, Assam University, Silchar 788011, Assam, India
| | - Supriyo Chakraborty
- Department of Biotechnology, Assam University, Silchar 788011, Assam, India.
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15
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Greenan E, Gallagher S, Khalil R, Murphy CC, Ní Gabhann-Dromgoole J. Advancing Our Understanding of Corneal Herpes Simplex Virus-1 Immune Evasion Mechanisms and Future Therapeutics. Viruses 2021; 13:v13091856. [PMID: 34578437 PMCID: PMC8473450 DOI: 10.3390/v13091856] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/24/2022] Open
Abstract
Herpes stromal keratitis (HSK) is a disease that commonly affects the cornea and external eye and is caused by Herpes Simplex Virus type 1 (HSV-1). This virus infects approximately 66% of people worldwide; however, only a small portion of these people will develop symptoms in their lifetime. There is no cure or vaccine available for HSV-1; however, there are treatments available that aim to control the inflammation caused by the virus and prevent its recurrence. While these treatments are beneficial to those suffering with HSK, there is a need for more effective treatments to minimise the need for topical steroids, which can have harmful effects, and to prevent bouts of disease reactivation, which can lead to progressive corneal scarring and visual impairment. This review details the current understanding of HSV-1 infection and discusses potential novel treatment options including microRNAs, TLRs, mAbs, and aptamers.
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Affiliation(s)
- Emily Greenan
- Department of Ophthalmology, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland; (E.G.); (C.C.M.)
- School of Pharmacy and Biomolecular Sciences (PBS), RSCI Research Institute, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland;
| | - Sophie Gallagher
- School of Biological and Health Sciences, Technological University (TU) Dublin, Kevin Street, D02 XK51 Dublin, Ireland;
| | - Rana Khalil
- School of Pharmacy and Biomolecular Sciences (PBS), RSCI Research Institute, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland;
| | - Conor C. Murphy
- Department of Ophthalmology, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland; (E.G.); (C.C.M.)
- Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland
| | - Joan Ní Gabhann-Dromgoole
- Department of Ophthalmology, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland; (E.G.); (C.C.M.)
- School of Pharmacy and Biomolecular Sciences (PBS), RSCI Research Institute, Royal College of Surgeons in Ireland, D02 XK51 Dublin, Ireland;
- Correspondence:
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16
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Afshari A, Yaghobi R, Rezaei G. Inter-regulatory role of microRNAs in interaction between viruses and stem cells. World J Stem Cells 2021; 13:985-1004. [PMID: 34567421 PMCID: PMC8422934 DOI: 10.4252/wjsc.v13.i8.985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are well known for post-transcriptional regulatory ability over specific mRNA targets. miRNAs exhibit temporal or tissue-specific expression patterns and regulate the cell and tissue developmental pathways. They also have determinative roles in production and differentiation of multiple lineages of stem cells and might have therapeutic advantages. miRNAs are a part of some viruses' regulatory machinery, not a byproduct. The trace of miRNAs was detected in the genomes of viruses and regulation of cell reprograming and viral pathogenesis. Combination of inter-regulatory systems has been detected for miRNAs during viral infections in stem cells. Contraction between viruses and stem cells may be helpful in therapeutic tactics, pathogenesis, controlling viral infections and defining stem cell developmental strategies that is programmed by miRNAs as a tool. Therefore, in this review we intended to study the inter-regulatory role of miRNAs in the interaction between viruses and stem cells and tried to explain the advantages of miRNA regulatory potentials, which make a new landscape for future studies.
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Affiliation(s)
- Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran.
| | - Ghazal Rezaei
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
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17
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Narożna M, Rubiś B. Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy. Int J Mol Sci 2021; 22:8663. [PMID: 34445368 PMCID: PMC8395427 DOI: 10.3390/ijms22168663] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/07/2021] [Accepted: 08/08/2021] [Indexed: 02/06/2023] Open
Abstract
Recently, we have experienced a serious pandemic. Despite significant technological advances in molecular technologies, it is very challenging to slow down the infection spread. It appeared that due to globalization, SARS-CoV-2 spread easily and adapted to new environments or geographical or weather zones. Additionally, new variants are emerging that show different infection potential and clinical outcomes. On the other hand, we have some experience with other pandemics and some solutions in virus elimination that could be adapted. This is of high importance since, as the latest reports demonstrate, vaccine technology might not follow the new, mutated virus outbreaks. Thus, identification of novel strategies and markers or diagnostic methods is highly necessary. For this reason, we present some of the latest views on SARS-CoV-2/COVID-19 therapeutic strategies and raise a solution based on miRNA. We believe that in the face of the rapidly increasing global situation and based on analogical studies of other viruses, the possibility of using the biological potential of miRNA technology is very promising. It could be used as a promising diagnostic and prognostic factor, as well as a therapeutic target and tool.
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Affiliation(s)
- Maria Narożna
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcickiego St., 60-781 Poznan, Poland;
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 49 Przybyszewskiego St., 60-355 Poznan, Poland
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18
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Luan X, Zhou X, Fallah P, Pandya M, Lyu H, Foyle D, Burch D, Diekwisch TGH. MicroRNAs: Harbingers and shapers of periodontal inflammation. Semin Cell Dev Biol 2021; 124:85-98. [PMID: 34120836 DOI: 10.1016/j.semcdb.2021.05.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/03/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023]
Abstract
Periodontal disease is an inflammatory reaction of the periodontal tissues to oral pathogens. In the present review we discuss the intricate effects of a regulatory network of gene expression modulators, microRNAs (miRNAs), as they affect periodontal morphology, function and gene expression during periodontal disease. These miRNAs are small RNAs involved in RNA silencing and post-transcriptional regulation and affect all stages of periodontal disease, from the earliest signs of gingivitis to the regulation of periodontal homeostasis and immunity and to the involvement in periodontal tissue destruction. MiRNAs coordinate periodontal disease progression not only directly but also through long non-coding RNAs (lncRNAs), which have been demonstrated to act as endogenous sponges or decoys that regulate the expression and function of miRNAs, and which in turn suppress the targeting of mRNAs involved in the inflammatory response, cell proliferation, migration and differentiation. While the integrity of miRNA function is essential for periodontal health and immunity, miRNA sequence variations (genetic polymorphisms) contribute toward an enhanced risk for periodontal disease progression and severity. Several polymorphisms in miRNA genes have been linked to an increased risk of periodontitis, and among those, miR-146a, miR-196, and miR-499 polymorphisms have been identified as risk factors for periodontal disease. The role of miRNAs in periodontal disease progression is not limited to the host tissues but also extends to the viruses that reside in periodontal lesions, such as herpesviruses (human herpesvirus, HHV). In advanced periodontal lesions, HHV infections result in the release of cytokines from periodontal tissues and impair antibacterial immune mechanisms that promote bacterial overgrowth. In turn, controlling the exacerbation of periodontal disease by minimizing the effect of periodontal HHV in periodontal lesions may provide novel avenues for therapeutic intervention. In summary, this review highlights multiple levels of miRNA-mediated control of periodontal disease progression, (i) through their role in periodontal inflammation and the dysregulation of homeostasis, (ii) as a regulatory target of lncRNAs, (iii) by contributing toward periodontal disease susceptibility through miRNA polymorphism, and (iv) as periodontal microflora modulators via viral miRNAs.
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Affiliation(s)
- Xianghong Luan
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA
| | - Xiaofeng Zhou
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, 801 South Paulina Street, Chicago, IL 60612, USA
| | - Pooria Fallah
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA
| | - Mirali Pandya
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA
| | - Huling Lyu
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA; Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China
| | - Deborah Foyle
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA
| | - Dan Burch
- Department of Pedodontics, TAMU College of Dentistry, 75246 Dallas, TX, USA
| | - Thomas G H Diekwisch
- Texas A&M Center for Craniofacial Research and Diagnosis and Department of Periodontics, TAMU College of Dentistry, 75246 Dallas, TX USA.
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19
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Shojaei Jeshvaghani Z, Arefian E, Asgharpour S, Soleimani M. Latency-Associated Transcript-Derived MicroRNAs in Herpes Simplex Virus Type 1 Target SMAD3 and SMAD4 in TGF-β/Smad Signaling Pathway. IRANIAN BIOMEDICAL JOURNAL 2021; 25:169-79. [PMID: 33546553 DOI: 10.29252/ibj.25.3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Background During its latent infection, hepatic stellate cell (HSV-1) produces only a micro RNA (miRNA) precursor called latency-associated transcript (LAT), which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs in targeting SMAD3 and SMAD4, as two main mediators in TGF-β/Smad. Methods The selection of LAT-derived miRNAs was based on the search results obtained from an online miRNA prediction tool. HEK293T cells were transfected with each miRNA-expressing lentivector and with the construct-expressing LAT. To survey the effect of LAT on the expression of pro-fibrotic markers, we transfected LX-2 cells with LAT construct. The impact of viral miRNA overexpression on SMADs and fibrotic markers was measured by quantitative PCR and luciferase assays. Results Among the LAT-derived miRNAs, miR-H2, miR-H3, and miR-H4 were selected for the study. Our results demonstrated that while miR-H2 binds to both SMAD mRNAs, miR-H3 and miR-H4 inhibit only the expression of the SMAD4 and SMAD3, respectively. Transfection of the LX-2 with LAT also decreased pro-fibrotic genes expression. Conclusion Our findings display that LAT negatively regulates TGF-β/Smad through targeting SMAD3 and SMAD4 by its miRNAs. These viral miRNAs can also contribute to the development of therapeutic interventions in diseases for which prevention or treatment can be achieved through targeting TGF-β pathway.
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Affiliation(s)
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | | | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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20
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Latency-Associated Transcript-Derived MicroRNAs in Herpes Simplex Virus Type 1 Target SMAD3 and SMAD4 in TGF-β/Smad Signaling Pathway. IRANIAN BIOMEDICAL JOURNAL 2021. [PMID: 33546553 PMCID: PMC8183387 DOI: 10.52547/ibj.25.3.169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: During its latent infection, HSV-1 produces only a miRNA precursor called LAT, which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs in targeting SMAD3 and SMAD4, as two main mediators in TGF-β/Smad. Methods: The selection of LAT-derived miRNAs was based on the search results obtained from an online miRNA prediction tool. HEK293T cells were transfected with each miRNA-expressing lentivector and with the construct-expressing LAT. To survey the effect of LAT on the expression of pro-fibrotic markers, we transfected LX-2 cells with LAT construct. The impact of viral miRNA overexpression on SMADs and fibrotic markers was measured by qPCR and luciferase assays. Results: Among the LAT-derived miRNAs, miR-H2, miR-H3, and miR-H4 were selected for the study. Our results demonstrated that while miR-H2 binds to both SMAD mRNAs, miR-H3 and miR-H4 inhibit only the expression of the SMAD4 and SMAD3, respectively. Transfection of the LX-2 with LAT also decreased pro-fibrotic genes expression. Conclusion: Our findings display that LAT negatively regulates TGF-β/Smad through targeting SMAD3 and SMAD4 by its miRNAs. These viral miRNAs can also contribute to the development of therapeutic interventions in diseases for which prevention or treatment can be achieved through targeting TGF-β pathway.
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21
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Liao Y, Zhuang G, Sun A, Khan OA, Lupiani B, Reddy SM. Marek's Disease Virus Cluster 3 miRNAs Restrict Virus' Early Cytolytic Replication and Pathogenesis. Viruses 2020; 12:v12111317. [PMID: 33212952 PMCID: PMC7698348 DOI: 10.3390/v12111317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 12/21/2022] Open
Abstract
Herpesvirus-encoded microRNAs (miRNAs) have been discovered in infected cells; however, lack of a suitable animal model has hampered functional analyses of viral miRNAs in vivo. Marek’s disease virus (MDV) (Gallid alphaherpesvirus 2, GaHV-2) genome contains 14 miRNA precursors, which encode 26 mature miRNAs, grouped into three clusters. In this study, the role of MDV-encoded cluster 3 miRNAs, also known as mdv1-miR-M8-M10, in pathogenesis was evaluated in chickens, the natural host of MDV. Our results show that deletion of cluster 3 miRNAs did not affect virus replication and plaque size in cell culture, but increased early cytolytic replication of MDV in chickens. We also observed that deletion of cluster 3 miRNAs resulted in significantly higher virus reactivation from peripheral blood lymphocytes. In addition, pathogenesis studies showed that deletion of cluster 3 miRNAs resulted in more severe atrophy of lymphoid organs and reduced mean death time, but did not affect the incidence of MDV-associated visceral tumors. We confirmed these results by generating a cluster 3 miRNA revertant virus in which the parental MDV phenotype was restored. To the best of our knowledge, our study provides the first evidence that MDV cluster 3 miRNAs play an important role in modulating MDV pathogenesis.
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22
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New Insights on the Mobility of Viral and Host Non-Coding RNAs Reveal Extracellular Vesicles as Intriguing Candidate Antiviral Targets. Pathogens 2020; 9:pathogens9110876. [PMID: 33114356 PMCID: PMC7690884 DOI: 10.3390/pathogens9110876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 12/27/2022] Open
Abstract
Intercellular communication occurring by cell-to-cell contacts and via secreted messengers trafficked through extracellular vehicles is critical for regulating biological functions of multicellular organisms. Recent research has revealed that non-coding RNAs can be found in extracellular vesicles consistent with a functional importance of these molecular vehicles in virus propagation and suggesting that these essential membrane-bound bodies can be highjacked by viruses to promote disease pathogenesis. Newly emerging evidence that coronaviruses generate non-coding RNAs and use extracellular vesicles to facilitate viral pathogenicity may have important implications for the development of effective strategies to combat COVID-19, a disease caused by infection with the novel coronavirus, SARS-CoV-2. This article provides a short overview of our current understanding of the interactions between non-coding RNAs and extracellular vesicles and highlights recent research which supports these interactions as potential therapeutic targets in the development of novel antiviral therapies.
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23
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Tribolet L, Kerr E, Cowled C, Bean AGD, Stewart CR, Dearnley M, Farr RJ. MicroRNA Biomarkers for Infectious Diseases: From Basic Research to Biosensing. Front Microbiol 2020; 11:1197. [PMID: 32582115 PMCID: PMC7286131 DOI: 10.3389/fmicb.2020.01197] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
In the pursuit of improved diagnostic tests for infectious diseases, several classes of molecules have been scrutinized as prospective biomarkers. Small (18–22 nucleotide), non-coding RNA transcripts called microRNAs (miRNAs) have emerged as promising candidates with extensive diagnostic potential, due to their role in numerous diseases, previously established methods for quantitation and their stability within biofluids. Despite efforts to identify, characterize and apply miRNA signatures as diagnostic markers in a range of non-infectious diseases, their application in infectious disease has advanced relatively slowly. Here, we outline the benefits that miRNA biomarkers offer to the diagnosis, management, and treatment of infectious diseases. Investigation of these novel biomarkers could advance the use of personalized medicine in infectious disease treatment, which raises important considerations for validating their use as diagnostic or prognostic markers. Finally, we discuss new and emerging miRNA detection platforms, with a focus on rapid, point-of-care testing, to evaluate the benefits and obstacles of miRNA biomarkers for infectious disease.
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Affiliation(s)
- Leon Tribolet
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Emily Kerr
- Institute for Frontier Materials, Deakin University, Geelong, VIC, Australia
| | - Christopher Cowled
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Andrew G D Bean
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Cameron R Stewart
- Health and Biosecurity, Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Megan Dearnley
- Diagnostics, Surveillance and Response (DSR), Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
| | - Ryan J Farr
- Diagnostics, Surveillance and Response (DSR), Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Geelong, VIC, Australia
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24
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Zou W, Zhou X, Wang L, Zhou GG, Chen X. Degradation of Herpes Simplex Virus-1 Viral miRNA H11 by Vaccinia Virus Protein VP55 Attenuates Viral Replication. Front Microbiol 2020; 11:717. [PMID: 32390978 PMCID: PMC7191008 DOI: 10.3389/fmicb.2020.00717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/27/2020] [Indexed: 11/19/2022] Open
Abstract
Among 29 distinct miRNAs expressed by the herpes simplex virus-1 (HSV-1) during lytic infection, miR-H11, together with miR-H1 to miR-H8 are reported to locate in the RNA-induced silencing complex (RISC). miR-H11 is encoded within viral origins of replication and lies entirely within the origins of replication. However, the roles of this miRNA derived from lytic infection with HSV-1 remain unclear. Using the advantage of vaccinia virus protein VP55 (VP55)-mediated degradation of miRNAs, we constructed a recombinant virus expressing VP55 (R5502) to demonstrate that: (1) accumulation of miR-H11 from R5502 was reduced by 540-fold versus that in cells infected with wild-type HSV-1, but miR-H1 to miR-H8 which also located in the RISC were not reduced significantly from R5502 compare with wild-type HSV-1; (2) downregulation of miR-H11 from R5502 infected cells results in markedly lower viral DNA synthesis compared with wild-type HSV-1; and (3) downregulation of miR-H11 also restricted viral spreading, and resulted in low accumulation of representative viral proteins and viral yields. The findings were confirmed through either using of a miR-H11 inhibitor or pre-transfection of a plasmid expressing VP55. These data suggest that miR-H11 plays a currently unidentified role in maintaining sufficient viral DNA synthesis during the course of viral infection.
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Affiliation(s)
- Weixuan Zou
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xusha Zhou
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lei Wang
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Grace Guoying Zhou
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Shenzhen International Institute for Biomedical Research, Shenzhen, China
| | - Xiaoqing Chen
- Shenzhen International Institute for Biomedical Research, Shenzhen, China
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25
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Mishra R, Kumar A, Ingle H, Kumar H. The Interplay Between Viral-Derived miRNAs and Host Immunity During Infection. Front Immunol 2020; 10:3079. [PMID: 32038626 PMCID: PMC6989438 DOI: 10.3389/fimmu.2019.03079] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/17/2019] [Indexed: 01/01/2023] Open
Abstract
MicroRNAs are short non-coding RNAs that play a crucial role in the regulation of gene expression during cellular processes. The host-encoded miRNAs are known to modulate the antiviral defense during viral infection. In the last decade, multiple DNA and RNA viruses have been shown to produce miRNAs known as viral miRNAs (v-miRNAs) so as to evade the host immune response. In this review, we highlight the origin and biogenesis of viral miRNAs during the viral lifecycle. We also explore the role of viral miRNAs in immune evasion and hence in maintaining chronic infection and disease. Finally, we offer insights into the underexplored role of viral miRNAs as potential targets for developing therapeutics for treating complex viral diseases.
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Affiliation(s)
- Richa Mishra
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
| | - Ashish Kumar
- Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Harshad Ingle
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
| | - Himanshu Kumar
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
- Laboratory of Host Defense, WPI Immunology, Frontier Research Centre, Osaka University, Osaka, Japan
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26
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Naqvi AR. Immunomodulatory roles of human herpesvirus-encoded microRNA in host-virus interaction. Rev Med Virol 2020; 30:e2081. [PMID: 31432608 PMCID: PMC7398577 DOI: 10.1002/rmv.2081] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 12/18/2022]
Abstract
Human herpesviruses (HHV) are large, double stranded, DNA viruses with high seroprevalence across the globe. Clinical manifestation of primary HHV infection resolve shortly, however, this period is prolonged in immunocompromised patients or individuals with suppressed immunity. Examining molecular mechanisms of HHV-encoded virulence factors can provide finer details of HHV-host interaction. A unique genetic feature of most members of HHV is that they encode multiple microRNAs (miR). In this review, I will provide mechanistic insights into the immunomodulatory functions of herpesvirus-encoded viral miR (v-miR) that favor viral persistence and spread by ingenious immune evasion schemes. Similar to host miR, v-miR can simultaneously regulate expression of multiple transcripts including host- and virus-derived. V-miRs, by virtue of their direct interaction with various transcripts, can regulate expression of critical components of host innate and adaptive immune system. V-miRs are also exported through exosomal route and gain entry into various cells even at distant sites, thereby allowing HHV to manipulate cellular and tissue immunity. Targeting v-miR may serve as a novel and promising therapeutic candidate to mitigate HHV-mediated clinical manifestations.
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Affiliation(s)
- Afsar R Naqvi
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
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27
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Analysis of hepatic and retinal cell microRNAome during AAV infection reveals their diverse impact on viral transduction and cellular physiology. Gene 2020; 724:144157. [DOI: 10.1016/j.gene.2019.144157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/25/2019] [Accepted: 10/04/2019] [Indexed: 12/18/2022]
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Yao L, Zhou Y, Sui Z, Zhang Y, Liu Y, Xie H, Gao H, Fan H, Zhang Y, Liu M, Li S, Tang H. HBV-encoded miR-2 functions as an oncogene by downregulating TRIM35 but upregulating RAN in liver cancer cells. EBioMedicine 2019; 48:117-129. [PMID: 31530503 PMCID: PMC6838411 DOI: 10.1016/j.ebiom.2019.09.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 08/24/2019] [Accepted: 09/06/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection has been well established as a high-risk factor for the carcinogenesis of hepatocellular carcinoma (HCC). Cellular microRNA (miRNA) is involved in tumorigenesis by accelerating the malignant phenotype in HCC. However, whether HBV can encode miRNAs that contribute to HCC is not entirely clear. METHODS In this study, an miRNA encoded by HBV (HBV-miR-2) was identified by Solexa sequencing in HBV-positive HCC specimens and further verified in serum samples from HCC patients with HBV infection and in HBV-positive HCC cell lines. To evaluate the roles of HBV-miR-2 in liver cancer cells, we determined cell viability and migration/invasion ability by gain-of-function experiment in HBV(-) liver cancer cells (HepG2 and Huh7) and loss-of-function experiments in Huh7 cells stably expressing HBV-miR-2 (Huh7/HBV-miR-2 cells) and HepG2.2.15 cells. Furthermore, to elucidate the mechanism by which HBV-miR-2 work on cell malignancy, we identified and studied the effect of two target genes (TRIM35 and RAN) of HBV-miR-2 in liver cancer cells. FINDINGS We revealed that HBV-miR-2 promoted HCC cell growth ability by suppressing apoptosis and promoting migration and invasion by enhancing the epithelial-mesenchymal transition (EMT), functioning as an oncogene in the development of HBV-related HCC. Furthermore, we demonstrated that HBV-miR-2 suppresses the expression of TRIM35 but enhances RAN expression by targeting their 3'-untranslated regions (3'UTR) and that the ectopic expression of TRIM35 or knockdown of RAN counteracted the malignant phenotypes induced by HBV-miR-2. INTERPRETATION Our findings indicate that an HBV-encoded miRNA, HBV-miR-2, promotes oncogenic activity by downregulating TRIM35 expression and upregulating RAN expression in liver cancer cells, likely providing insight into tumorigenesis in HBV-related liver cancer. FUND: This work was supported in part by the National Natural Science Foundation of China (No: 81830094; 91629302; 31270818) and the Natural Science Foundation of Tianjin (No: 12JCZDJC25100).
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Affiliation(s)
- Lili Yao
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Yadi Zhou
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Zhenhua Sui
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Yanling Zhang
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Yankun Liu
- The Cancer Institute, Tangshan People's Hospital, Tangshan 063001, China
| | - Hong Xie
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China.
| | - Huijie Gao
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Hongxia Fan
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Yi Zhang
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Min Liu
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
| | - Shengping Li
- State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Hua Tang
- Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China.
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Herpes Simplex Virus Type 1-Encoded miR-H2-3p Manipulates Cytosolic DNA-Stimulated Antiviral Innate Immune Response by Targeting DDX41. Viruses 2019; 11:v11080756. [PMID: 31443275 PMCID: PMC6723821 DOI: 10.3390/v11080756] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 07/28/2019] [Accepted: 08/06/2019] [Indexed: 12/17/2022] Open
Abstract
Herpes simplex virus type 1 (HSV-1), one of the human pathogens widely epidemic and transmitted among various groups of people in the world, often causes symptoms known as oral herpes or lifelong asymptomatic infection. HSV-1 employs many sophisticated strategies to escape host antiviral immune response based on its multiple coding proteins. However, the functions involved in the immune evasion of miRNAs encoded by HSV-1 during lytic (productive) infection remain poorly studied. Dual-luciferase reporter gene assay and bioinformatics revealed that Asp-Glu-Ala-Asp (DEAD)-box helicase 41 (DDX41), a cytosolic DNA sensor of the DNA-sensing pathway, was a putative direct target gene of HSV-1-encoded miR-H2-3p. The transfection of miR-H2-3p mimics inhibited the expression of DDX41 at the level of mRNA and protein, as well as the expression of interferon beta (IFN-β) and myxoma resistance protein I (MxI) induced by HSV-1 infection in THP-1 cells, and promoted the viral replication and its gene transcription. However, the transfection of miR-H2-3p inhibitor showed opposite effects. This finding indicated that HSV-1-encoded miR-H2-3p attenuated cytosolic DNA-stimulated antiviral immune response by manipulating host DNA sensor molecular DDX41 to enhance virus replication in cultured cells.
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30
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Huang R, Zhou X, Ren S, Liu X, Han Z, Zhou GG. Effect of Loss-of-function of the Herpes Simplex Virus-1 microRNA H6-5p on Virus Replication. Virol Sin 2019; 34:386-396. [PMID: 31020575 PMCID: PMC6687794 DOI: 10.1007/s12250-019-00111-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/28/2019] [Indexed: 12/31/2022] Open
Abstract
To date, 29 distinct microRNAs (miRNAs) have been reported to be expressed during herpes simplex virus infections. Sequence analysis of mature herpes simplex virus-1 (HSV-1) miRNAs revealed five sets of miRNAs that are complementary to each other: miR-H6-5p/H1-3p, miR-H6-3p/H1-5p, H2-5p/H14-3p, miR-H2-3p/H14-5p, and miR-H7/H27. However, the roles of individual miRNAs and consequences of this complementarity remain unclear. Here, we focus on two of these complementary miRNAs, miR-H6-5p and miR-H1-3p, using loss-of-function experiments in vitro and in a mouse model of infection using an miRNA sponge approach, including tandem multiplex artificial miRNA-binding sequences that do not match perfectly to the target miRNA inserted downstream of a green fluorescent protein reporter gene. Infection with recombinant virus expressing the miR-H6-5p sponge reduced viral protein levels and virus yield. Decreased accumulation of viral proteins was also observed at early stages of infection in the presence of both an miR-H6-5p inhibitor and plasmid-expressed miR-H1-3p. Moreover, establishment of latency and reactivation did not differ between the recombinant virus expressing the miR-H6-5p sponge and wild-type HSV-1. Taken together, these data suggest that miR-H6-5p has an as-yet-unidentified role in the early stages of viral infection, and its complement miR-H1-3p suppresses this role in later stages of infection. This report extends understanding of the roles of miRNAs in infection by herpes simplex viruses, supporting a model of infection in which the production of virus and its virulent effects are tightly controlled to maximize persistence in the host and population.
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Affiliation(s)
- Rongquan Huang
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xusha Zhou
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shuqi Ren
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xianjie Liu
- Shenzhen International Institute for Biomedical Research, Shenzhen, 518116, China
| | - Zhiyuan Han
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Grace Guoying Zhou
- Shenzhen International Institute for Biomedical Research, Shenzhen, 518116, China.
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31
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Sun B, Wang Q, Pan D. [Mechanisms of herpes simplex virus latency and reactivation]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2019; 48:89-101. [PMID: 31102363 PMCID: PMC8800643 DOI: 10.3785/j.issn.1008-9292.2019.02.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 11/20/2018] [Indexed: 06/09/2023]
Abstract
Herpes simplex virus (HSV), including HSV-1 and HSV-2, is an important pathogen that can cause many diseases. Usually these diseases are recurrent and incurable. After lytic infection on the surface of peripheral mucosa, HSV can enter sensory neurons and establish latent infection during which viral replication ceases. Moreover, latent virus can re-enter the replication cycle by reactivation and return to peripheral tissues to start recurrent infection. This ability to escape host immune surveillance during latent infection and to spread during reactivation is a viral survival strategy and the fundamental reason why no drug can completely eradicate the virus at present. Although there are many studies on latency and reactivation of HSV, and much progress has been made, many specific mechanisms of the process remain obscure or even controversial due to the complexity of this process and the limitations of research models. This paper reviews the major results of research on HSV latency and reactivation, and discusses future research directions in this field.
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Affiliation(s)
- Boqiang Sun
- Department of Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qiongyan Wang
- Department of Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Dongli Pan
- Department of Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou 310058, China
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32
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Baruah V, Bose S. Computational identification of hepatitis E virus-encoded microRNAs and their targets in human. J Med Virol 2019; 91:1545-1552. [PMID: 30919453 DOI: 10.1002/jmv.25471] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 02/13/2019] [Accepted: 03/12/2019] [Indexed: 12/26/2022]
Abstract
microRNAs (miRNAs) are small, noncoding RNAs which regulate eukaryotic gene expression via RNA interference pathway. Recently, miRNAs have been identified in a number of viruses with current evidence suggesting that they regulate gene expression in both virus and host. This makes viral miRNAs potential targets of clinical intervention, with the possibility of inhibiting aberrant host gene expression associated with the disease. In this study, computational approaches were taken to scan the hepatitis E virus (HEV) genome for putative pre-miRNA molecules, which were then analyzed for the presence of mature miRNAs. The 3'-untranslated region (3'-UTR) and 5'-UTR sequences targeted by these miRNAs were identified using Miranda computational tool, followed by the functional annotation of the associated messenger RNAs (mRNAs) using Gene Ontology terms and Kyoto Encyclopaedia of Genes and Genomes pathway analysis. We identified a total of nine viral encoded miRNAs in HEV. After functional annotation, the majority of the viral miRNA targets were found to be associated with cell cycle, cell differentiation, nitrogen compound metabolism, transmembrane transport, and chromosome organization. This in-silico study identified putative viral miRNAs encoded by HEV and their potential human mRNAs targets. These viral miRNAs have the potential to affect host gene expression as well as viral life cycle and pathogenesis and can, therefore, serve as potential therapeutic targets during HEV infection.
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Affiliation(s)
- Vargab Baruah
- Department of Biotechnology, Gauhati University, Guwahati, Assam, India
| | - Sujoy Bose
- Department of Biotechnology, Gauhati University, Guwahati, Assam, India
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Hussein HAM, Alfhili MA, Pakala P, Simon S, Hussain J, McCubrey JA, Akula SM. miRNAs and their roles in KSHV pathogenesis. Virus Res 2019; 266:15-24. [PMID: 30951791 DOI: 10.1016/j.virusres.2019.03.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/26/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman Disease (MCD). Recent mechanistic advances have discerned the importance of microRNAs in the virus-host relationship. KSHV has two modes of replication: lytic and latent phase. KSHV entry into permissive cells, establishment of infection, and maintenance of latency are contingent upon successful modulation of the host miRNA transcriptome. Apart from host cell miRNAs, KSHV also encodes viral miRNAs. Among various cellular and molecular targets, miRNAs are appearing to be key players in regulating viral pathogenesis. Therefore, the use of miRNAs as novel therapeutics has gained considerable attention as of late. This innovative approach relies on either mimicking miRNA species by identical oligonucleotides, or selective silencing of miRNA with specific oligonucleotide inhibitors. Here, we provide an overview of KSHV pathogenesis at the molecular level with special emphasis on the various roles miRNAs play during virus infection.
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Affiliation(s)
- Hosni A M Hussein
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States; Faculty of Science, Al Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Mohammad A Alfhili
- Department of Medicine (Division of Hematology/Oncology), Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
| | - Pranaya Pakala
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Sandra Simon
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Jaffer Hussain
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Shaw M Akula
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States.
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Herpes Simplex Virus 1 Lytic Infection Blocks MicroRNA (miRNA) Biogenesis at the Stage of Nuclear Export of Pre-miRNAs. mBio 2019; 10:mBio.02856-18. [PMID: 30755517 PMCID: PMC6372804 DOI: 10.1128/mbio.02856-18] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Various mechanisms have been identified by which viruses target host small RNA biogenesis pathways to achieve optimal infection outcomes. Herpes simplex virus 1 (HSV-1) is a ubiquitous human pathogen whose successful persistence in the host entails both productive (“lytic”) and latent infection. Although many HSV-1 miRNAs have been discovered and some are thought to help control the lytic/latent switch, little is known about regulation of their biogenesis. By characterizing expression of both pre-miRNAs and mature miRNAs under various conditions, this study revealed striking differences in miRNA biogenesis between lytic and latent infection and uncovered a regulatory mechanism that blocks pre-miRNA nuclear export and is dependent on viral protein ICP27 and viral DNA synthesis. This mechanism represents a new virus-host interaction that could limit the repressive effects of HSV-1 miRNAs hypothesized to promote latency and may shed light on the regulation of miRNA nuclear export, which has been relatively unexplored. Herpes simplex virus 1 (HSV-1) switches between two infection programs, productive (“lytic”) and latent infection. Some HSV-1 microRNAs (miRNAs) have been hypothesized to help control this switch, and yet little is known about regulation of their expression. Using Northern blot analyses, we found that, despite inherent differences in biogenesis efficiency among six HSV-1 miRNAs, all six exhibited high pre-miRNA/miRNA ratios during lytic infection of different cell lines and, when detectable, in acutely infected mouse trigeminal ganglia. In contrast, considerably lower ratios were observed in latently infected ganglia and in cells transduced with lentiviral vectors expressing the miRNAs, suggesting that HSV-1 lytic infection blocks miRNA biogenesis. This phenomenon is not specific to viral miRNAs, as a host miRNA expressed from recombinant HSV-1 also exhibited high pre-miRNA/miRNA ratios late during lytic infection. The levels of most of the mature miRNAs remained stable during infection in the presence of actinomycin D, indicating that the high ratios are due to inefficient pre-miRNA conversion to miRNA. Cellular fractionation experiments showed that late (but not early) during infection, pre-miRNAs were enriched in the nucleus and depleted in the cytoplasm, indicating that nuclear export was blocked. A mutation eliminating ICP27 expression or addition of acyclovir reduced pre-miRNA/miRNA ratios, but mutations drastically reducing Us11 expression did not. Thus, HSV-1 lytic infection inhibits miRNA biogenesis at the step of nuclear export and does so in an ICP27- and viral DNA synthesis-dependent manner. This mechanism may benefit the virus by reducing expression of repressive miRNAs during lytic infection while permitting elevated expression during latency.
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Cokarić Brdovčak M, Zubković A, Jurak I. Herpes Simplex Virus 1 Deregulation of Host MicroRNAs. Noncoding RNA 2018; 4:ncrna4040036. [PMID: 30477082 PMCID: PMC6316616 DOI: 10.3390/ncrna4040036] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/15/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023] Open
Abstract
Viruses utilize microRNAs (miRNAs) in a vast variety of possible interactions and mechanisms, apparently far beyond the classical understanding of gene repression in humans. Likewise, herpes simplex virus 1 (HSV-1) expresses numerous miRNAs and deregulates the expression of host miRNAs. Several HSV-1 miRNAs are abundantly expressed in latency, some of which are encoded antisense to transcripts of important productive infection genes, indicating their roles in repressing the productive cycle and/or in maintenance/reactivation from latency. In addition, HSV-1 also exploits host miRNAs to advance its replication or repress its genes to facilitate latency. Here, we discuss what is known about the functional interplay between HSV-1 and the host miRNA machinery, potential targets, and the molecular mechanisms leading to an efficient virus replication and spread.
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Affiliation(s)
- Maja Cokarić Brdovčak
- Laboratory for Molecular Virology, Department of Biotechnology, University of Rijeka, R. Matejčić 2, HR-51000 Rijeka, Croatia.
| | - Andreja Zubković
- Laboratory for Molecular Virology, Department of Biotechnology, University of Rijeka, R. Matejčić 2, HR-51000 Rijeka, Croatia.
| | - Igor Jurak
- Laboratory for Molecular Virology, Department of Biotechnology, University of Rijeka, R. Matejčić 2, HR-51000 Rijeka, Croatia.
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36
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Naqvi AR, Shango J, Seal A, Shukla D, Nares S. Herpesviruses and MicroRNAs: New Pathogenesis Factors in Oral Infection and Disease? Front Immunol 2018; 9:2099. [PMID: 30319604 PMCID: PMC6170608 DOI: 10.3389/fimmu.2018.02099] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 08/24/2018] [Indexed: 12/28/2022] Open
Abstract
The oral cavity incessantly encounters a plethora of microorganisms. Effective and efficient oral innate and adaptive immune responses are incumbent to maintain healthy mucosa. A higher prevalence of Human Herpesviruses (HHV), a family of large enveloped DNA viruses, has been reported in multiple oral inflammatory diseases suggesting their involvement in disease progression. However, the viral components contributing to oral disease remain obscure. MicroRNAs (miRNA) are non-protein coding, single stranded ribonucleic acid (RNA) molecules that post-transcriptionally regulate diverse messenger RNAs. Thus, miRNAs can control large repertoire of biological processes. Changes in miRNA expression are associated with various oral infections and diseases. Cellular miRNAs can act as pro- or anti-viral factors and dysregulation of host miRNA expression occurs during herpesviruses infection. This strongly suggest a critical role of cellular miRNAs in host-herpesvirus interaction. Interestingly, HHV also encode multiple miRNAs (called viral miRNAs) that may play key role in host-pathogen interaction by modulating both host biological pathways and controlling viral life cycle. Recent studies from our laboratory have identified viral miRNAs (v-miRs) in diseased oral tissue biopsies and demonstrate their immunomodulatory roles. This review discusses the association of miRNAs (both host and viral) and herpesviruses in the pathogenesis of oral inflammatory diseases.
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Affiliation(s)
- Afsar R Naqvi
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Jennifer Shango
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Alexandra Seal
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Deepak Shukla
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States.,Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, Chicago, IL, United States
| | - Salvador Nares
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
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Kanokudom S, Mahony TJ, Smith DR, Assavalapsakul W. Modulation of bovine herpesvirus 1 infection by virally encoded microRNAs. Virus Res 2018; 257:1-6. [PMID: 30193942 DOI: 10.1016/j.virusres.2018.08.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/24/2018] [Accepted: 08/31/2018] [Indexed: 12/27/2022]
Abstract
Bovine herpesvirus 1 (BoHV-1), is a member of the subfamily Alphaherpesvirinae in the order Herpesviridae and is a ubiquitous pathogen of cattle responsible for significant economic loss worldwide. The BoHV-1 genome encodes at least 10 BoHV-1 microRNA (miRNA) genes, whose functions remain poorly understood. This study sought to understand the role of three BoHV-1 miRNA genes, Bhv1-miR-B6, Bhv1-miR-B8 and Bhv1-miR-B9, which are located proximal to the BoHV-1 origins of replication (OriS). Therefore, plasmids expressing the precursor miRNA hairpins for the Bhv1-miR-B6, Bhv1-miR-B8, and Bhv1-miR-B9 genes were constructed and transfected into Madin-Darby bovine kidney cells prior to BoHV-1 infection. Interestingly, transient expression of either Bhv1-miR-B8 or Bhv1-miR-B9 in Madin-Darby bovine kidney cells prior to infection resulted in partial suppression of BoHV-1 replication, quantified through estimating levels of glycoprotein C mRNA and protein levels. Putative interactions between the mature miRNA bhv1-miR-B8-3p and bhv1-miR-B9 and BoHV-1 transcripts were identified providing plausible pathways for these molecules to affect virus replication. Therefore, these two miRNAs are implicated in the post-transcriptional regulation of BoHV-1 transcripts important for virus replication and could be used to limit BoHV-1 replication.
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Affiliation(s)
- Sitthichai Kanokudom
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Timothy J Mahony
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Duncan R Smith
- Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakornpathom, 73170, Thailand
| | - Wanchai Assavalapsakul
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
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38
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Zheng K, Liu Q, Wang S, Ren Z, Kitazato K, Yang D, Wang Y. HSV-1-encoded microRNA miR-H1 targets Ubr1 to promote accumulation of neurodegeneration-associated protein. Virus Genes 2018. [DOI: 10.1007/s11262-018-1551-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chiang JJ, Sparrer KMJ, van Gent M, Lässig C, Huang T, Osterrieder N, Hopfner KP, Gack MU. Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity. Nat Immunol 2018; 19:53-62. [PMID: 29180807 PMCID: PMC5815369 DOI: 10.1038/s41590-017-0005-y] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 10/16/2017] [Indexed: 12/25/2022]
Abstract
The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.
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MESH Headings
- Animals
- Cells, Cultured
- Chlorocebus aethiops
- DEAD Box Protein 58/immunology
- DEAD Box Protein 58/metabolism
- Gene Expression/immunology
- HEK293 Cells
- Herpesvirus 1, Human/immunology
- Herpesvirus 1, Human/physiology
- Host-Pathogen Interactions/immunology
- Humans
- Immunity/immunology
- Interferon Type I/genetics
- Interferon Type I/immunology
- Interferon Type I/metabolism
- Mice, Knockout
- Pseudogenes/genetics
- RNA Transport/immunology
- RNA, Ribosomal, 5S/genetics
- RNA, Ribosomal, 5S/immunology
- RNA, Ribosomal, 5S/metabolism
- Receptors, Immunologic
- Vero Cells
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Affiliation(s)
- Jessica J Chiang
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | | | - Michiel van Gent
- Department of Microbiology, The University of Chicago, Chicago, IL, USA
| | - Charlotte Lässig
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Teng Huang
- Institut für Virologie, Freie Universität Berlin, Berlin, Germany
| | | | - Karl-Peter Hopfner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
- Center for Integrated Protein Science Munich, Munich, Germany
| | - Michaela U Gack
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
- Department of Microbiology, The University of Chicago, Chicago, IL, USA.
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40
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Are miRNAs critical determinants in herpes simplex virus pathogenesis? Microbes Infect 2017; 20:461-465. [PMID: 29287990 DOI: 10.1016/j.micinf.2017.12.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/11/2017] [Indexed: 12/21/2022]
Abstract
miRNAs are small noncoding RNA that play a crucial role in gene regulation by inhibiting translation or promoting mRNA degradation. Viruses themselves express miRNAs that can target either the host or viral mRNA transcriptome. Moreover, viral infection of cells causes a drastic change in host miRNAs. This complex interaction between the host and viruses often favors the virus to evade immune elimination and favors the establishment and maintenance of latency. In this review we discuss the function of both host and viral miRNAs in regulating herpes simplex virus pathogenesis and also discuss the prospect of using miRNAs as biomarkers and therapeutic tools.
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41
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Enk J, Levi A, Weisblum Y, Yamin R, Charpak-Amikam Y, Wolf DG, Mandelboim O. HSV1 MicroRNA Modulation of GPI Anchoring and Downstream Immune Evasion. Cell Rep 2017; 17:949-956. [PMID: 27760325 PMCID: PMC5081403 DOI: 10.1016/j.celrep.2016.09.077] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 06/28/2016] [Accepted: 09/22/2016] [Indexed: 12/24/2022] Open
Abstract
Herpes simplex virus 1 (HSV1) is a ubiquitous human pathogen that utilizes variable mechanisms to evade immune surveillance. The glycosylphosphatidylinositol (GPI) anchoring pathway is a multistep process in which a myriad of different proteins are covalently attached to a GPI moiety to be presented on the cell surface. Among the different GPI-anchored proteins there are many with immunological importance. We present evidence that the HSV1-encoded miR H8 directly targets PIGT, a member of the protein complex that covalently attaches proteins to GPI in the final step of GPI anchoring. This results in a membrane down-modulation of several different immune-related, GPI-anchored proteins, including ligands for natural killer-activating receptors and the prominent viral restriction factor tetherin. Thus, we suggest that by utilizing just one of dozens of miRNAs encoded by HSV1, the virus can counteract the host immune response at several key points.
HSV1 miR H8 targets PIGT of the GPI anchoring pathway Expression of the anti-viral protein tetherin is reduced and viral spread enhanced Expression of GPI-anchored activating NK cell ligands is reduced Recognition and elimination by NK cells decrease
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Affiliation(s)
- Jonatan Enk
- The Lautenberg Center of General and Tumor Immunology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
| | - Assi Levi
- Photodermatosis Clinic and Laser Unit, Dermatology Department, Rabin Medical Center, Petah Tikva 4941492, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Yiska Weisblum
- Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; Department of Biochemistry and the Chanock Center for Virology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
| | - Rachel Yamin
- The Lautenberg Center of General and Tumor Immunology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
| | - Yoav Charpak-Amikam
- The Lautenberg Center of General and Tumor Immunology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel
| | - Dana G Wolf
- Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Ofer Mandelboim
- The Lautenberg Center of General and Tumor Immunology, IMRIC, The Hebrew University Faculty of Medicine, Jerusalem 91120, Israel.
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42
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Tian Z, Zhang J, He H, Li J, Wu Y, Shen Z. MiR-525-3p mediates antiviral defense to rotavirus infection by targeting nonstructural protein 1. Biochim Biophys Acta Mol Basis Dis 2017; 1863:3212-3225. [PMID: 28890396 DOI: 10.1016/j.bbadis.2017.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 09/05/2017] [Accepted: 09/06/2017] [Indexed: 12/23/2022]
Abstract
MicroRNAs (miRNAs) are short RNAs of approximately 22 nucleotides that post-transcriptionally regulate gene expression by controlling mRNA stability or translation. They play critical roles in intricate networks of host-pathogen interactions and innate immunity. Rotaviruses (RVs) are the leading cause of severe diarrhea among infants and young children worldwide. This study was undertaken to demonstrate the importance of cellular miRNAs during RV (human Wa RV or Rhesus RV) strains infection. Twenty-nine differentially regulated miRNAs were identified during RV infection, and miR-525-3p was downregulated and validated by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-525-3p mimic inhibited RV replication in dose-dependent manner. Correspondingly, the miR-525-3p inhibitors enhanced RV replication. We confirmed that miR-525-3p was complementary to the 3' untranslated region (UTR) of nonstructural protein 1(NSP1) of RV (Wa or Rhesus) strains. Interestingly, miR-525-3p induced type I interferon (IFN) expression and proinflammatory cytokines during RV infection through IFN regulatory factor (IRF) 3/IRF7 and NF-κB activation, which can induce an antiviral state to further suppress RV infection. In addition, RV suppressed miR-525-3p expression to evade host innate immunity through the action of the RV protein NSP1. These results suggest that miR-525-3p has the potential to be used as an antiviral therapeutic against RV infection.
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Affiliation(s)
- Zhiqiang Tian
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, China
| | - Ji Zhang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, China
| | - Haiyang He
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, China
| | - Jintao Li
- Institute of Tropical Medicine, Third Military Medical University, Chongqing, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, China..
| | - Zigang Shen
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, China..
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43
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Kim H, Iizasa H, Kanehiro Y, Fekadu S, Yoshiyama H. Herpesviral microRNAs in Cellular Metabolism and Immune Responses. Front Microbiol 2017; 8:1318. [PMID: 28769892 PMCID: PMC5513955 DOI: 10.3389/fmicb.2017.01318] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022] Open
Abstract
The microRNAs (miRNAs) function as a key regulator in many biological processes through post-transcriptional suppression of messenger RNAs. Recent advancements have revealed that miRNAs are involved in many biological functions of cells. Not only host cells, but also some viruses encode miRNAs in their genomes. Viral miRNAs regulate cell proliferation, differentiation, apoptosis, and the cell cycle to establish infection and produce viral progeny. Particularly, miRNAs encoded by herpes virus families play integral roles in persistent viral infection either by regulation of metabolic processes or the immune response of host cells. The life-long persistent infection of gamma herpes virus subfamilies, such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, induces host cells to malignant transformation. The unbalanced metabolic processes and evasion from host immune surveillance by viral miRNAs are induced either by direct targeting of key proteins or indirect regulation of multiple signaling pathways. We provide an overview of the pathogenic roles of viral miRNAs in cellular metabolism and immune responses during herpesvirus infection.
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Affiliation(s)
- Hyoji Kim
- Department of Microbiology, Faculty of Medicine, Shimane UniversityShimane, Japan
| | - Hisashi Iizasa
- Department of Microbiology, Faculty of Medicine, Shimane UniversityShimane, Japan
| | - Yuichi Kanehiro
- Department of Microbiology, Faculty of Medicine, Shimane UniversityShimane, Japan
| | - Sintayehu Fekadu
- Department of Microbiology, Faculty of Medicine, Shimane UniversityShimane, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Faculty of Medicine, Shimane UniversityShimane, Japan
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44
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Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication. J Virol 2017; 91:JVI.01919-16. [PMID: 28148795 DOI: 10.1128/jvi.01919-16] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV+ hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection.IMPORTANCE Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.
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45
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Identification and characterization of two putative microRNAs encoded by Bombyx mori cypovirus. Virus Res 2017; 233:86-94. [DOI: 10.1016/j.virusres.2017.03.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/03/2017] [Accepted: 03/04/2017] [Indexed: 01/23/2023]
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46
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Phelan D, Barrozo ER, Bloom DC. HSV1 latent transcription and non-coding RNA: A critical retrospective. J Neuroimmunol 2017; 308:65-101. [PMID: 28363461 DOI: 10.1016/j.jneuroim.2017.03.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 03/02/2017] [Accepted: 03/02/2017] [Indexed: 12/22/2022]
Abstract
Virologists have invested great effort into understanding how the herpes simplex viruses and their relatives are maintained dormant over the lifespan of their host while maintaining the poise to remobilize on sporadic occasions. Piece by piece, our field has defined the tissues in play (the sensory ganglia), the transcriptional units (the latency-associated transcripts), and the responsive genomic region (the long repeats of the viral genomes). With time, the observed complexity of these features has compounded, and the totality of viral factors regulating latency are less obvious. In this review, we compose a comprehensive picture of the viral genetic elements suspected to be relevant to herpes simplex virus 1 (HSV1) latent transcription by conducting a critical analysis of about three decades of research. We describe these studies, which largely involved mutational analysis of the notable latency-associated transcripts (LATs), and more recently a series of viral miRNAs. We also intend to draw attention to the many other less characterized non-coding RNAs, and perhaps coding RNAs, that may be important for consideration when trying to disentangle the multitude of phenotypes of the many genetic modifications introduced into recombinant HSV1 strains.
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Affiliation(s)
- Dane Phelan
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, United States.
| | - Enrico R Barrozo
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, United States.
| | - David C Bloom
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, United States.
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47
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Induction of Multiple miR-200/182 Members in the Brains of Mice Are Associated with Acute Herpes Simplex Virus 1 Encephalitis. PLoS One 2017; 12:e0169081. [PMID: 28045967 PMCID: PMC5207681 DOI: 10.1371/journal.pone.0169081] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 12/12/2016] [Indexed: 12/21/2022] Open
Abstract
Important roles of microRNAs (miRNAs) in regulating the host response during viral infection have begun to be defined. However, little is known about the functional roles of miRNAs within an in vivo acute viral encephalitis model. We therefore identified global changes in miRNA expression during acute herpes simplex virus type 1 (HSV-1) encephalitis (HSVE) in mice. We found that many of the highly upregulated miRNAs (miR-155, miR-146a and miR-15b) detected in HSV-1 infected brain tissue are known regulators of inflammation and innate immunity. We also observed upregulation of 7 members belonging to the related group of miRNAs, the miR-200 family and miR-182 cluster (miR-200/182). Using in situ hybridization, we found that these miRNAs co-localized to regions of the brain with severe HSVE-related pathology and were upregulated in various cell types including neurons. Induction was apparent but not limited to cells in which HSV-1 was detected by immunohistochemistry, suggesting possible roles of these miRNAs in the host response to viral-induced tissue damage. Bioinformatic prediction combined with gene expression profiling revealed that the induced miR-200/182 members could regulate the biosynthesis of heparan sulfate proteoglycans. Using luciferase assays, we found that miR-96, miR-141, miR-183 and miR-200c all potentially targeted the syndecan-2 gene (Sdc2), which codes for a cell surface heparan sulfate proteoglycan involved in HSV-1 cellular attachment and entry.
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48
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Zhong S, Naqvi A, Bair E, Nares S, Khan AA. Viral MicroRNAs Identified in Human Dental Pulp. J Endod 2016; 43:84-89. [PMID: 27939730 DOI: 10.1016/j.joen.2016.10.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 10/01/2016] [Accepted: 10/07/2016] [Indexed: 02/08/2023]
Abstract
INTRODUCTION MicroRNAs (miRs) are a family of noncoding RNAs that regulate gene expression. They are ubiquitous among multicellular eukaryotes and are also encoded by some viruses. Upon infection, viral miRs (vmiRs) can potentially target gene expression in the host and alter the immune response. Although prior studies have reported viral infections in human pulp, the role of vmiRs in pulpal disease is yet to be explored. The purpose of this study was to examine the expression of vmiRs in normal and diseased pulps and to identify potential target genes. METHODS Total RNA was extracted and quantified from normal and inflamed human pulps (N = 28). Expression profiles of vmiRs were then interrogated using miRNA microarrays (V3) and the miRNA Complete Labeling and Hyb Kit (Agilent Technologies, Santa Clara, CA). To identify vmiRs that were differentially expressed, we applied a permutation test. RESULTS Of the 12 vmiRs detected in the pulp, 4 vmiRs (including those from herpesvirus and human cytomegalovirus) were differentially expressed in inflamed pulp compared with normal pulp (P < .05). Using bioinformatics, we identified potential target genes for the differentially expressed vmiRs. They included key mediators involved in the detection of microbial ligands, chemotaxis, proteolysis, cytokines, and signal transduction molecules. CONCLUSIONS These data suggest that miRs may play a role in interspecies regulation of pulpal health and disease. Further research is needed to elucidate the mechanisms by which vmiRs can potentially modulate the host response in pulpal disease.
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Affiliation(s)
- Sheng Zhong
- Endodontic Associates, Minneapolis, Minnesota; Department of Endodontics, University of North Carolina, Chapel Hill, North Carolina
| | - Afsar Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois
| | - Eric Bair
- Department of Endodontics, University of North Carolina, Chapel Hill, North Carolina
| | - Salvador Nares
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois
| | - Asma A Khan
- Department of Endodontics, University of North Carolina, Chapel Hill, North Carolina.
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49
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Piedade D, Azevedo-Pereira JM. The Role of microRNAs in the Pathogenesis of Herpesvirus Infection. Viruses 2016; 8:v8060156. [PMID: 27271654 PMCID: PMC4926176 DOI: 10.3390/v8060156] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/25/2016] [Accepted: 05/30/2016] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs important in gene regulation. They are able to regulate mRNA translation through base-pair complementarity. Cellular miRNAs have been involved in the regulation of nearly all cellular pathways, and their deregulation has been associated with several diseases such as cancer. Given the importance of microRNAs to cell homeostasis, it is no surprise that viruses have evolved to take advantage of this cellular pathway. Viruses have been reported to be able to encode and express functional viral microRNAs that target both viral and cellular transcripts. Moreover, viral inhibition of key proteins from the microRNA pathway and important changes in cellular microRNA pool have been reported upon viral infection. In addition, viruses have developed multiple mechanisms to avoid being targeted by cellular microRNAs. This complex interaction between host and viruses to control the microRNA pathway usually favors viral infection and persistence by either reducing immune detection, avoiding apoptosis, promoting cell growth, or promoting lytic or latent infection. One of the best examples of this virus-host-microRNA interplay emanates from members of the Herperviridae family, namely the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), human herpesvirus 8 (HHV-8), and the Epstein–Barr virus (EBV). In this review, we will focus on the general functions of microRNAs and the interactions between herpesviruses, human hosts, and microRNAs and will delve into the related mechanisms that contribute to infection and pathogenesis.
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Affiliation(s)
- Diogo Piedade
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
| | - José Miguel Azevedo-Pereira
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
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50
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Abstract
Alphaherpesviruses infect a variety of species from sea turtles to man and can cause significant disease in mammals including humans and livestock. These viruses are characterized by a lytic and latent state in nerve ganglia, with the ability to establish a lifelong latent infection that is interrupted by periodic reactivation. Previously, it was accepted that latency was a dominant state and that only during relatively infrequent reactivation episodes did latent genomes within ganglia become transcriptionally active. Here, we review recent data, focusing mainly on Herpes Simplex Virus type 1 which indicate that the latent state is more dynamic than recently appreciated.
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Affiliation(s)
- David C Bloom
- Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
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