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Shifflett KW, Dittmer DP. Mouse models of Kaposi sarcoma-associated herpesvirus (KSHV). Virology 2025; 603:110384. [PMID: 39837218 PMCID: PMC11788063 DOI: 10.1016/j.virol.2024.110384] [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: 10/27/2024] [Revised: 12/18/2024] [Accepted: 12/29/2024] [Indexed: 01/23/2025]
Abstract
Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is a prerequisite for the development of several human cancers, including Kaposi sarcoma and primary effusion lymphoma. Efficient long-term infection with KSHV and subsequent virally induced cell transformation is limited to humans, resulting in a lack of small animal models for KSHV-driven malignancies. Various attempts to create a mouse model for KSHV include infection of humanized mice, generating transgenic mice that ectopically express viral proteins, and grafting KSHV-infected tumor, primary, or immortalized cells onto immunodeficient mice. While no single mouse model can recapitulate the full range of KSHV-associated pathologies described in humans, each model adds an essential piece to the complete picture of KSHV infection and oncogenesis.
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Affiliation(s)
- Kyle W Shifflett
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, USA
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, USA.
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2
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Ortega JA, Liang Z, Xu JK, Gottwein E. Retargeting target-directed microRNA-decay sites to highly expressed viral or cellular miRNAs. Nucleic Acids Res 2024; 52:14171-14183. [PMID: 39588775 DOI: 10.1093/nar/gkae1103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 10/21/2024] [Accepted: 10/25/2024] [Indexed: 11/27/2024] Open
Abstract
MicroRNAs (miRNAs) are pervasive regulators of gene expression, necessitating the development of tools to inhibit individual miRNAs for functional studies or therapeutic targeting. Specialized base-pairing configurations between a miRNA and an RNA target site can trigger the degradation of the targeting miRNA through target-directed miRNA decay (TDMD). Previous work has identified several natural sites that induce TDMD of specific miRNAs. We explored retargeting known TDMD sites for the inhibition of heterologous miRNAs, including several encoded by Kaposi's Sarcoma-associated herpesvirus (KSHV). We focused particularly on miR-K11, a viral mimic of the oncogenic miRNA miR-155. miRNA pairing architectures based on the TDMD site in the long non-coding RNA Cyrano outperformed other retargeted sites. Cyrano-like inhibitors were specific for viral miR-K11 over cellular miR-155 and vice versa. Lentiviral delivery of a Cyrano-like miR-K11 inhibitor into KSHV-transformed primary effusion lymphoma (PEL) cells impaired their viability, showing that miR-K11 promotes KSHV-dependent PEL cell survival. Surprisingly, inactivation of ZSWIM8, a key mediator of TDMD, did not substantially affect miRNA inhibition by retargeted Cyrano-based inhibitors in 293T or PEL cells. Together, our results demonstrate the feasibility of retargeting natural TDMD sites to highly expressed viral or cellular miRNAs and further define features of effective encoded miRNA inhibitors.
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Affiliation(s)
- Jesus A Ortega
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Tarry 6-735, Chicago, IL 60611, USA
| | - Ziyan Liang
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Tarry 6-735, Chicago, IL 60611, USA
| | - Junpeng Kenny Xu
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Tarry 6-735, Chicago, IL 60611, USA
| | - Eva Gottwein
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Tarry 6-735, Chicago, IL 60611, USA
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3
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Yu CJ, Damania B. Molecular Mechanisms of Kaposi Sarcoma-Associated Herpesvirus (HHV8)-Related Lymphomagenesis. Cancers (Basel) 2024; 16:3693. [PMID: 39518131 PMCID: PMC11544871 DOI: 10.3390/cancers16213693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Approximately 15-20% of cancers are caused by viruses. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an oncogenic virus that is the etiologic agent of not only Kaposi sarcoma but also the lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV can infect a broad tropism of cells, including B lymphocytes, wherein KSHV encodes specific viral proteins that can transform the cell. KSHV infection precedes the progression of PEL and MCD. KSHV establishes lifelong infection and has two phases of its lifecycle: latent and lytic. During the latent phase, viral genomes are maintained episomally with limited gene expression. Upon sporadic reactivation, the virus enters its replicative lytic phase to produce infectious virions. KSHV relies on its viral products to modulate host factors to evade immune detection or to co-opt their function for KSHV persistence. These manipulations dysregulate normal cell pathways to ensure cell survival and inhibit antiviral immune responses, which in turn, contribute to KSHV-associated malignancies. Here, we highlight the known molecular mechanisms of KSHV that promote lymphomagenesis and how these findings identify potential therapeutic targets for KSHV-associated lymphomas.
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Affiliation(s)
| | - Blossom Damania
- Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;
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4
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Sin SH, Eason AB, Kim Y, Schneider JW, Damania B, Dittmer DP. The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice. Cell Host Microbe 2024; 32:755-767.e4. [PMID: 38653242 PMCID: PMC11305081 DOI: 10.1016/j.chom.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 01/16/2024] [Accepted: 03/27/2024] [Indexed: 04/25/2024]
Abstract
Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.
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Affiliation(s)
- Sang-Hoon Sin
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anthony B Eason
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yongbaek Kim
- Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Johann W Schneider
- National Health Laboratory Service, Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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5
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Wang T, Zheng J, Pan Y, Zhuang Z, Zeng Y. Investigation of key miRNAs and Target-mRNA in Kaposi's sarcoma using bioinformatic methods. Heliyon 2024; 10:e29502. [PMID: 38660282 PMCID: PMC11041027 DOI: 10.1016/j.heliyon.2024.e29502] [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: 10/05/2023] [Revised: 04/09/2024] [Accepted: 04/09/2024] [Indexed: 04/26/2024] Open
Abstract
Kaposi's sarcoma (KS) is the second most common tumor in human immunodeficiency virus (HIV) infected patients worldwide. While many miRNAs have been confirmed to be involved in KS biological processes, no relevant studies have combined miRNA and mRNA expression profiles using KS patient tissue biopsies. In this study, we performed transcriptome sequencing on tumor and normal tissues from four KS patients and identified differentially expressed mRNA and miRNA, further performed target gene prediction and enrichment analysis. 19,551 target-mRNAs were identified by predicting 106 miRNAs, with 553 overlapping with 571 significantly differentially expressed mRNAs. Enrichment analysis showed significant involvement of the Ubiquitin-mediated proteolysis pathway. Additionally, the miRNA-mRNA interaction network was established, and the topological score of Cytohubba's algorithm was calculated for comparison with three other datasets. The Mutual Clustering Coefficient (MCC) scoring ranking placed ZBTB34, NFIB, and RORA as the top three mRNAs, while hsa-miR-16-5p, hsa-miR-27a-3p, hsa-miR-340-5p, hsa-miR-182-5p, and hsa-miR-186-5p ranked as the top five miRNAs. Hsa-miR-101-3p is the only miRNA that appears both in the top 10 MCC scores and at the intersection of the other two datasets. Finally, qRT-PCR was used to validate the findings at the cellular level. In summary, the miRNA analysis results indicated that hsa-miR-101-3p could be used as a potential diagnostic or therapeutic marker in future studies. Moreover, the mRNA analysis results suggested that the histone binding pathways involved in mRNAs and ubiquitin-related biological processes were closely associated with KS and could serve as promising biomarkers for the diagnosis and treatment of this disease.
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Affiliation(s)
- Tianye Wang
- Precision Clinical Laboratory, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Jun Zheng
- Precision Clinical Laboratory, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yangyang Pan
- Precision Clinical Laboratory, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zhaowei Zhuang
- Precision Clinical Laboratory, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yan Zeng
- Precision Clinical Laboratory, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
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6
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Zhang Y, Guo W, Zhan Z, Bai O. Carcinogenic mechanisms of virus-associated lymphoma. Front Immunol 2024; 15:1361009. [PMID: 38482011 PMCID: PMC10932979 DOI: 10.3389/fimmu.2024.1361009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/12/2024] [Indexed: 04/17/2024] Open
Abstract
The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.
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Affiliation(s)
| | | | | | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
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7
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Diggins NL, Hancock MH. Viral miRNA regulation of host gene expression. Semin Cell Dev Biol 2023; 146:2-19. [PMID: 36463091 PMCID: PMC10101914 DOI: 10.1016/j.semcdb.2022.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
Viruses have evolved a multitude of mechanisms to combat barriers to productive infection in the host cell. Virally-encoded miRNAs are one such means to regulate host gene expression in ways that benefit the virus lifecycle. miRNAs are small non-coding RNAs that regulate protein expression but do not trigger the adaptive immune response, making them powerful tools encoded by viruses to regulate cellular processes. Diverse viruses encode for miRNAs but little sequence homology exists between miRNAs of different viral species. Despite this, common cellular pathways are targeted for regulation, including apoptosis, immune evasion, cell growth and differentiation. Herein we will highlight the viruses that encode miRNAs and provide mechanistic insight into how viral miRNAs aid in lytic and latent infection by targeting common cellular processes. We also highlight how viral miRNAs can mimic host cell miRNAs as well as how viral miRNAs have evolved to regulate host miRNA expression. These studies dispel the myth that viral miRNAs are subtle regulators of gene expression, and highlight the critical importance of viral miRNAs to the virus lifecycle.
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Affiliation(s)
- Nicole L Diggins
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA
| | - Meaghan H Hancock
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA.
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8
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Gorbea C, Elhakiem A, Cazalla D. Shaping the host cell environment with viral noncoding RNAs. Semin Cell Dev Biol 2023; 146:20-30. [PMID: 36581481 PMCID: PMC10101873 DOI: 10.1016/j.semcdb.2022.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/24/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022]
Abstract
Just like the cells they infect viruses express different classes of noncoding RNAs (ncRNAs). Viral ncRNAs come in all shapes and forms, and they usually associate with cellular proteins that are important for their functions. Viral ncRNAs have diverse functions, but they all contribute to the viral control of the cellular environment. Viruses utilize ncRNAs to regulate viral replication, to decide whether they should remain latent or reactivate, to evade the host immune responses, or to promote cellular transformation. In this review we describe the diverse functions played by different classes of ncRNAs expressed by adenoviruses and herpesviruses, how they contribute to the viral infection, and how their study led to insights into RNA-based mechanisms at play in host cells.
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Affiliation(s)
- Carlos Gorbea
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Abdalla Elhakiem
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Demián Cazalla
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
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9
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Mohanty S, Harhaj EW. Mechanisms of Innate Immune Sensing of HTLV-1 and Viral Immune Evasion. Pathogens 2023; 12:735. [PMID: 37242405 PMCID: PMC10221045 DOI: 10.3390/pathogens12050735] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Human T lymphotropic virus-1 (HTLV-1) was the first identified oncoretrovirus, which infects and establishes a persistent infection in approximately 10-20 million people worldwide. Although only ~5% of infected individuals develop pathologies such as adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disorder termed HTLV-1-asssociated myelopathy/tropical spastic paraparesis (HAM/TSP), asymptomatic carriers are more susceptible to opportunistic infections. Furthermore, ATLL patients are severely immunosuppressed and prone to other malignancies and other infections. The HTLV-1 replication cycle provides ligands, mainly nucleic acids (RNA, RNA/DNA intermediates, ssDNA intermediates, and dsDNA), that are sensed by different pattern recognition receptors (PRRs) to trigger immune responses. However, the mechanisms of innate immune detection and immune responses to HTLV-1 infection are not well understood. In this review, we highlight the functional roles of different immune sensors in recognizing HTLV-1 infection in multiple cell types and the antiviral roles of host restriction factors in limiting persistent infection of HTLV-1. We also provide a comprehensive overview of intricate strategies employed by HTLV-1 to subvert the host innate immune response that may contribute to the development of HTLV-1-associated diseases. A more detailed understanding of HTLV-1-host pathogen interactions may inform novel strategies for HTLV-1 antivirals, vaccines, and treatments for ATLL or HAM/TSP.
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Affiliation(s)
- Suchitra Mohanty
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033, USA;
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Melnik BC, Stadler R, Weiskirchen R, Leitzmann C, Schmitz G. Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma. Int J Mol Sci 2023; 24:ijms24076102. [PMID: 37047075 PMCID: PMC10094152 DOI: 10.3390/ijms24076102] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/05/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023] Open
Abstract
Epidemiological evidence supports an association between cow’s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant’s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow’s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal “proliferation-dominated” B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.
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Kandeel M. Oncogenic Viruses-Encoded microRNAs and Their Role in the Progression of Cancer: Emerging Targets for Antiviral and Anticancer Therapies. Pharmaceuticals (Basel) 2023; 16:ph16040485. [PMID: 37111242 PMCID: PMC10146417 DOI: 10.3390/ph16040485] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/18/2023] [Accepted: 03/21/2023] [Indexed: 04/29/2023] Open
Abstract
Approximately 20% of all cases of human cancer are caused by viral infections. Although a great number of viruses are capable of causing a wide range of tumors in animals, only seven of these viruses have been linked to human malignancies and are presently classified as oncogenic viruses. These include the Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), human herpesvirus 8 (HHV8), and human T-cell lymphotropic virus type 1 (HTLV-1). Some other viruses, such as the human immunodeficiency virus (HIV), are associated with highly oncogenic activities. It is possible that virally encoded microRNAs (miRNAs), which are ideal non-immunogenic tools for viruses, play a significant role in carcinogenic processes. Both virus-derived microRNAs (v-miRNAs) and host-derived microRNAs (host miRNAs) can influence the expression of various host-derived and virus-derived genes. The current literature review begins with an explanation of how viral infections might exert their oncogenic properties in human neoplasms, and then goes on to discuss the impact of diverse viral infections on the advancement of several types of malignancies via the expression of v-miRNAs. Finally, the role of new anti-oncoviral therapies that could target these neoplasms is discussed.
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Affiliation(s)
- Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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12
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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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13
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Rangel-Ramírez VV, González-Sánchez HM, Lucio-García C. Exosomes: from biology to immunotherapy in infectious diseases. Infect Dis (Lond) 2023; 55:79-107. [PMID: 36562253 DOI: 10.1080/23744235.2022.2149852] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Exosomes are extracellular vesicles derived from the endosomal compartment, which are released by all kinds of eukaryotic and prokaryotic organisms. These vesicles contain a variety of biomolecules that differ both in quantity and type depending on the origin and cellular state. Exosomes are internalized by recipient cells, delivering their content and thus contributing to cell-cell communication in health and disease. During infections exosomes may exert a dual role, on one hand, they can transmit pathogen-related molecules mediating further infection and damage, and on the other hand, they can protect the host by activating the immune response and reducing pathogen spread. Selective packaging of pathogenic components may mediate these effects. Recently, quantitative analysis of samples by omics technologies has allowed a deep characterization of the proteins, lipids, RNA, and metabolite cargoes of exosomes. Knowledge about the content of these vesicles may facilitate their therapeutic application. Furthermore, as exosomes have been detected in almost all biological fluids, pathogenic or host-derived components can be identified in liquid biopsies, making them suitable for diagnosis and prognosis. This review attempts to organize the recent findings on exosome composition and function during viral, bacterial, fungal, and protozoan infections, and their contribution to host defense or to pathogen spread. Moreover, we summarize the current perspectives and future directions regarding the potential application of exosomes for prophylactic and therapeutic purposes.
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Affiliation(s)
| | | | - César Lucio-García
- Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, México
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14
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Luo T, Pan Y, Liu Y, Zheng J, Zhuang Z, Ren Z, Zhu J, Gu Y, Zeng Y. LANA regulates miR-155/GATA3 signaling axis by enhancing c-Jun/c-Fos interaction to promote the proliferation and migration of KSHV-infected cells. J Med Virol 2023; 95:e28255. [PMID: 36284455 DOI: 10.1002/jmv.28255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/08/2022] [Accepted: 10/21/2022] [Indexed: 01/11/2023]
Abstract
Kaposi's sarcoma (KS) is the second most common tumor in people infected with human immunodeficiency virus worldwide, but its pathogenesis is still unclear. In this study, we discovered that the expression of GATA-binding protein 3 (GATA3) was lowly expressed in KS tissues and KSHV-infected cells, while microRNA-155 (miR-155) was highly expressed in KS serum and KSHV-infected cells. miR-155 promoted the proliferation, migration and invasion of KSHV infection by targeting GATA3. Further, The KSHV-encoded protein, the Latency associated nuclear antigen (LANA), promotes the proliferation, migration and invasion of KSHV-infected cells by regulating the miR-155/GATA3 axis. Regarding the molecular mechanism, c-Jun and c-Fos interact to form a complex. LANA upregulates the expression of c-Jun and c-Fos and enhances the formation of c-Jun/c-Fos complex. The complex binds to the -95∼-100 bp site of miR-155 promoter and transcriptionally activates miR-155. All in all, LANA enhances the c-Jun/c-Fos interaction, resulting in enhanced transcriptional regulation of miR-155 by the c-Jun/c-Fos complex, thereby downregulating GATA3 and promoting the proliferation, migration and invasion of KSHV-infected cells. The discovery of LANA/c-Jun/c-Fos/miR-155/GATA3 further refines the pathogenesis of KS, potentially opening a new avenue for developing effective drugs against KS.
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Affiliation(s)
- Ting Luo
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yangyang Pan
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yuhao Liu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Jun Zheng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zhaowei Zhuang
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zuodong Ren
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Jiaojiao Zhu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yongqing Gu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yan Zeng
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
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15
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Meseguer S, Rubio MP, Lainez B, Pérez-Benavente B, Pérez-Moraga R, Romera-Giner S, García-García F, Martinez-Macias O, Cremades A, Iborra FJ, Candelas-Rivera O, Almazan F, Esplugues E. SARS-CoV-2-encoded small RNAs are able to repress the host expression of SERINC5 to facilitate viral replication. Front Microbiol 2023; 14:1066493. [PMID: 36876111 PMCID: PMC9978209 DOI: 10.3389/fmicb.2023.1066493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/26/2023] [Indexed: 02/18/2023] Open
Abstract
Serine incorporator protein 5 (SERINC5) is a key innate immunity factor that operates in the cell to restrict the infectivity of certain viruses. Different viruses have developed strategies to antagonize SERINC5 function but, how SERINC5 is controlled during viral infection is poorly understood. Here, we report that SERINC5 levels are reduced in COVID-19 patients during the infection by SARS-CoV-2 and, since no viral protein capable of repressing the expression of SERINC5 has been identified, we hypothesized that SARS-CoV-2 non-coding small viral RNAs (svRNAs) could be responsible for this repression. Two newly identified svRNAs with predicted binding sites in the 3'-untranslated region (3'-UTR) of the SERINC5 gene were characterized and we found that the expression of both svRNAs during the infection was not dependent on the miRNA pathway proteins Dicer and Argonaute-2. By using svRNAs mimic oligonucleotides, we demonstrated that both viral svRNAs can bind the 3'UTR of SERINC5 mRNA, reducing SERINC5 expression in vitro. Moreover, we found that an anti-svRNA treatment to Vero E6 cells before SARS-CoV-2 infection recovered the levels of SERINC5 and reduced the levels of N and S viral proteins. Finally, we showed that SERINC5 positively controls the levels of Mitochondrial Antiviral Signalling (MAVS) protein in Vero E6. These results highlight the therapeutic potential of targeting svRNAs based on their action on key proteins of the innate immune response during SARS-CoV-2 viral infection.
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Affiliation(s)
- Salvador Meseguer
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Mari-Paz Rubio
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Begoña Lainez
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Beatriz Pérez-Benavente
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Raúl Pérez-Moraga
- Bioinformatics and Biostatistics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Sergio Romera-Giner
- Bioinformatics and Biostatistics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Francisco García-García
- Bioinformatics and Biostatistics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | | | | | - Francisco J Iborra
- Biological Noise and Cell Plasticity Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Associated Unit to Instituto de Biomedicina de Valencia-CSIC, Valencia, Spain
| | - Oscar Candelas-Rivera
- Molecular and Cellular Biology Department, Centro Nacional de Biotecnología (CNB), CSIC, Madrid, Spain
| | - Fernando Almazan
- Molecular and Cellular Biology Department, Centro Nacional de Biotecnología (CNB), CSIC, Madrid, Spain
| | - Enric Esplugues
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.,Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, United States
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16
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Hardin LT, Xiao N. miRNAs: The Key Regulator of COVID-19 Disease. Int J Cell Biol 2022; 2022:1645366. [PMID: 36345541 PMCID: PMC9637033 DOI: 10.1155/2022/1645366] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 09/30/2022] [Indexed: 01/12/2024] Open
Abstract
As many parts of the world continue to fight the innumerable waves of COVID-19 infection, SARS-CoV-2 continues to sculpt its antigenic determinants to enhance its virulence and evolvability. Several vaccines were developed and used around the world, and oral antiviral medications are being developed against SARS-CoV-2. However, studies showed that the virus is mutating in line with the antibody's neutralization escape; thus, new therapeutic alternatives are solicited. We hereby review the key role that miRNAs can play as epigenetic mediators of the cross-talk between SARS-CoV-2 and the host cells. The limitations resulting from the "virus intelligence" to escape and antagonize the host miRNAs as well as the possible mechanisms that could be used in the viral evasion strategies are discussed. Lastly, we suggest new therapeutic approaches based on viral miRNAs.
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Affiliation(s)
- Leyla Tahrani Hardin
- Department of Biomedical Sciences at the Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, 94103 CA, USA
| | - Nan Xiao
- Department of Biomedical Sciences at the Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, 94103 CA, USA
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17
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Kuehnle N, Gottwein E. Druggable host gene dependencies in primary effusion lymphoma. Curr Opin Virol 2022; 56:101270. [PMID: 36182745 PMCID: PMC10043043 DOI: 10.1016/j.coviro.2022.101270] [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: 03/17/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/20/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). Here, we review what is known about human gene essentiality in PEL-derived cell lines. We provide an updated list of PEL-specific human gene dependencies, based on the improved definition of core essential genes across human cancer types. The requirements of PEL cell lines for interferon regulatory factor 4 (IRF4), basic leukine zipper ATF-like transcription factor (BATF), G1/S cyclin D2 (CCND2), CASP8 and FADD like apoptosis regulator (CFLAR), MCL1 apoptosis regulator (MCL1), and murine double minute 2 (MDM2) have been confirmed experimentally. KSHV co-opts IRF4 and BATF to drive superenhancer (SE)-mediated expression of IRF4 itself, MYC, and CCND2. IRF4 dependency of SE-mediated gene expression is shared with Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) and human T-cell leukemia virus type 1-transformed adult T-cell leukemia/lymphoma (ATLL) cell lines, as well as several B-cell lymphomas of nonviral etiology. LCLs and ATLL cell lines similarly share dependencies on CCND2 and CFLAR with PEL, but also have distinct gene dependencies. Genetic dependencies could be exploited for therapeutic intervention in PEL and other cancers.
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Affiliation(s)
- Neil Kuehnle
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Eva Gottwein
- Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
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18
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Viral Encoded miRNAs in Tumorigenesis: Theranostic Opportunities in Precision Oncology. Microorganisms 2022; 10:microorganisms10071448. [PMID: 35889167 PMCID: PMC9321719 DOI: 10.3390/microorganisms10071448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.
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19
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MicroRNA Regulation of Human Herpesvirus Latency. Viruses 2022; 14:v14061215. [PMID: 35746686 PMCID: PMC9231095 DOI: 10.3390/v14061215] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 12/04/2022] Open
Abstract
Herpesviruses are ubiquitous human pathogens. After productive (lytic) infection, all human herpesviruses are able to establish life-long latent infection and reactivate from it. Latent infection entails suppression of viral replication, maintenance of the viral genome in infected cells, and the ability to reactivate. Most human herpesviruses encode microRNAs (miRNAs) that regulate these processes during latency. Meanwhile, cellular miRNAs are hijacked by herpesviruses to participate in these processes. The viral or cellular miRNAs either directly target viral transcripts or indirectly affect viral infection through host pathways. These findings shed light on the molecular determinants that control the lytic-latent switch and may lead to novel therapeutics targeting latent infection. We discuss the multiple mechanisms by which miRNAs regulate herpesvirus latency, focusing on the patterns in these mechanisms.
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20
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Cesarman E, Chadburn A, Rubinstein PG. KSHV/HHV8-mediated hematologic diseases. Blood 2022; 139:1013-1025. [PMID: 34479367 PMCID: PMC8854683 DOI: 10.1182/blood.2020005470] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/08/2021] [Indexed: 11/20/2022] Open
Abstract
Kaposi sarcoma (KS) herpesvirus (KSHV), also known as human herpesvirus 8, is the causal agent of KS but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extracavitary (EC) PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV+ diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. These different KSHV-associated diseases may co-occur and may have overlapping features. KSHV, similar to Epstein-Barr virus (EBV), is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immunecompromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in KSHV+ EBV+ PEL/EC-PEL. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the 2 most common KSHV-associated lymphoid proliferations, including viral associations, patterns of viral gene expression, and cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding of KSHV biology, clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.
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Affiliation(s)
- Ethel Cesarman
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Amy Chadburn
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Paul G Rubinstein
- Section of Hematology/Oncology, Department of Medicine, John H. Stroger Jr Hospital of Cook County, Chicago, IL; and
- Department of Medicine, Ruth M. Rothstein CORE Center, Rush University Medical Center, Chicago, IL
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21
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Nakanishi K. Are Argonaute-Associated Tiny RNAs Junk, Inferior miRNAs, or a New Type of Functional RNAs? Front Mol Biosci 2021; 8:795356. [PMID: 34926585 PMCID: PMC8678501 DOI: 10.3389/fmolb.2021.795356] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/01/2021] [Indexed: 11/14/2022] Open
Abstract
The biosynthesis pathways of microRNAs (miRNAs) have been well characterized with the identification of the required components. miRNAs are synthesized from the transcripts of miRNA genes and other RNAs, such as introns, transfer RNAs, ribosomal RNAs, small nucleolar RNAs, and even viral miRNAs. These small RNAs are loaded into Argonaute (AGO) proteins and recruit the effector complexes to target mRNAs, repressing their gene expression post-transcriptionally. While mature miRNAs were defined as 19–23 nucleotides (nt), tiny RNAs (tyRNAs) shorter than 19 nt have been found to bind AGOs as equivalent or lesser miRNAs compared to their full-length mature miRNAs. In contrast, my recent study revealed that when human AGO3 loads 14 nt cleavage-inducing tyRNAs (cityRNAs), comprised of the first 14 nt of their corresponding mature miRNA, it can become a comparable slicer to AGO2. This observation raises the possibility that tyRNAs play distinct roles from their mature form. This minireview focuses on human AGO-associated tyRNAs shorter than 19 nt and discusses their possible biosynthesis pathways and physiological benefits, including how tyRNAs could avoid target-directed miRNA degradation accompanied by AGO polyubiquitination.
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Affiliation(s)
- Kotaro Nakanishi
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States.,Center for RNA Biology, Columbus, OH, United States
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22
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Valverde A, Seal A, Nares S, Shukla D, Naqvi AR. Human herpesvirus-encoded MicroRNA in host-pathogen interaction. Adv Biol Regul 2021; 82:100829. [PMID: 34560402 PMCID: PMC11646283 DOI: 10.1016/j.jbior.2021.100829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/28/2021] [Accepted: 09/13/2021] [Indexed: 11/17/2022]
Abstract
Human herpesviruses (HHV) are ubiquitous, linear dsDNA viruses that establish lifelong latency, disrupted by sporadic reactivation. HHV have evolved diverse ingenious mechanisms to evade robust host defenses. Incorporation of unique stem loop sequences that generate viral microRNAs (v-miRs) exemplifies one such evolutionary adaptation in HHV. These noncoding RNAs can control cellular and viral transcriptomes highlighting their ability in shaping host-HHV interactions. We summarize recent developments in functional characterization of HHV-encoded miRNAs in shaping the outcome of host-pathogen interaction. Non-immunogenic dissemination of v-miRs through exosomes confer added advantage to HHV in incessant modulation of host microenvironment. This review delineates the mechanistic role of v-miRs in facilitating viral persistence and tropism by targeting genes associated with cellular (apoptosis, angiogenesis, cell migration, etc.) and viral life cycle (latency, lytic and reactivation). Burgeoning evidences indicate plausible association of v-miRs in various immune-mediated diseases (nasopharyngeal carcinoma, neurological disorders, periodontal diseases, etc.) and herpesvirus-related malignancies indicating their broad-spectrum impact on host cellular pathways. We propose to exploit tisssue and systemic levels of v-miRs as diagnostic and prognostic markers for cancers and immune-mediated diseases. Therapeutic targeting of v-miRs will advance the promising outcomes of preclinical discoveries to bedside application.
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Affiliation(s)
- Araceli Valverde
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Alexandra Seal
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States
| | - Salvador Nares
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, 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
| | - Afsar Raza Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, United States.
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23
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Wang Y, Lin S, Zhao Z, Xu P, Gao K, Qian H, Zhang Z, Guo X. Functional analysis of a putative Bombyx mori cypovirus miRNA BmCPV-miR-10 and its effect on virus replication. INSECT MOLECULAR BIOLOGY 2021; 30:552-565. [PMID: 34296485 DOI: 10.1111/imb.12725] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 06/13/2023]
Abstract
Bombyx mori cypovirus (BmCPV) is an important pathogen of silkworm (B. mori), the economically beneficial insect. The mechanism of its interaction with host immune defence system in the process of infection is still not yet completely clear. Researches have demonstrated that virus-encoded microRNAs (miRNA) play a crucial role in regulating host-pathogen interaction, but few reports are available so far on miRNAs encoded by insect viruses, especially the RNA viruses. In this study, a putative miRNA encoded by the 10th segment of BmCPV genomic RNA, BmCPV-miR-10, was identified and functionally analysed. The expression of the putative BmCPV-miR-10 could be detected via stem-loop RT-PCR (reverse transcription-Polymerase Chain Reaction) in the midgut of silkworm larvae infected with BmCPV. BmCSDE1 (B. mori cold shock domain E1 protein) gene was predicted to be a candidate target gene for BmCPV-miR-10 with the miRNA binding site located in 3' untranslated region of its mRNA. The regulation effect of the putative BmCPV-miR-10 on BmCSDE1 was verified in HEK293 cells by lentiviral expression system, in BmN cells by transfecting BmCPV-miR-10 mimics. The qRT-PCR (quantitative real-time PCR) results showed that the putative BmCPV-miR-10 could suppress the expression of BmCSDE1. By injection of BmCPV-miR-10 mimics into the silkworm larvae infected with BmCPV, it was further proved that the putative BmCPV-miR-10 could suppress the expression of BmCSDE1 in vivo, then inhibit the expression of BmApaf-1 (B. mori apoptotic protease activating factor 1), while enhance the replication of BmCPV genomic RNAs to a certain extent. These results implied that the putative BmCPV-miR-10 could down-regulate the expression of BmCSDE1, then suppress the expression of BmApaf-1, thereby created a favourable intracellular environment for virus replication and proliferation.
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Affiliation(s)
- Y Wang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - S Lin
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - Z Zhao
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - P Xu
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - K Gao
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - H Qian
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericulture Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Z Zhang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - X Guo
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericulture Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
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24
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A structured RNA motif locks Argonaute2:miR-122 onto the 5' end of the HCV genome. Nat Commun 2021; 12:6836. [PMID: 34824224 PMCID: PMC8616905 DOI: 10.1038/s41467-021-27177-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/27/2021] [Indexed: 12/03/2022] Open
Abstract
microRNAs (miRNAs) form regulatory networks in metazoans. Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR-122 stabilizes the viral RNA and regulates viral translation. Here, we investigate the structural basis for these activities, taking into consideration that miRNAs function in complex with Argonaute (Ago) proteins. The crystal structure of the Ago2:miR-122:HCV complex reveals a structured RNA motif that traps Ago2 on the viral RNA, masking its 5’ end from enzymatic attack. The trapped Ago2 can recruit host factor PCBP2, implicated in viral translation, while binding of a second Ago2:miR-122 competes with PCBP2, creating a potential molecular switch for translational control. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex. The RNA genome of the Hepatitis C Virus binds to the liver-specific miR122. Here the authors report the crystal structure of the Ago2:miR122:HCV complex showing that the viral RNA’s structural element traps the Ago2:miR-122 complex on the 5’ end of the viral genome to protect it from degradation.
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25
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Han B, García‐Mendoza D, van den Berg H, van den Brink NW. Modulatory Effects of Mercury (II) Chloride (HgCl 2 ) on Chicken Macrophage and B-Lymphocyte Cell Lines with Viral-Like Challenges In Vitro. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2021; 40:2813-2824. [PMID: 34288095 PMCID: PMC9291928 DOI: 10.1002/etc.5169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/28/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
Mercury (Hg) is a toxic trace metal ubiquitously distributed in the environment. Inorganic mercury (as HgCl2 ) can cause immunotoxicity in birds, but the mechanisms of action are still not fully resolved, especially with respect to responses to viral infections. To investigate the potential immunomodulatory effects of Hg2+ on specific cell types of the avian immune system, chicken macrophage (HD-11) and B-lymphocyte (DT40) cell lines were applied as in vitro models for the innate and adaptive immune systems, respectively. The cells were stimulated with synthetic double-stranded RNA, which can be recognized by toll-like receptor-3 to mimic a viral infection. The Hg2+ showed concentration-dependent cytotoxicity in both cell lines, with similar median effect concentrations at 30 µM. The cytotoxicity of Hg2+ was closely related to glutathione (GSH) depletion and reactive oxygen species induction, whereas the de novo synthesis of GSH acted as a primary protective strategy. Nitric oxide produced by activated macrophages was strongly inhibited by Hg2+ , and was also influenced by cellular GSH levels. Cell proliferation, gene expression of microRNA-155, and cellular IgM levels in B cells were decreased at noncytotoxic Hg2+ concentrations. The secretion of antiviral interferon-α was induced by Hg2+ in both cell lines. Overall, our results suggest that Hg2+ exposure can cause immunomodulatory effects in birds by disrupting immune cell proliferation and cytokine production, and might result in disorders of the avian immune system. Environ Toxicol Chem 2021;40:2813-2824. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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Affiliation(s)
- Biyao Han
- Division of Toxicology, Wageningen University and ResearchWageningenThe Netherlands
| | - Diego García‐Mendoza
- Division of Toxicology, Wageningen University and ResearchWageningenThe Netherlands
| | - Hans van den Berg
- Division of Toxicology, Wageningen University and ResearchWageningenThe Netherlands
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26
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Vilimova M, Contrant M, Randrianjafy R, Dumas P, Elbasani E, Ojala P, Pfeffer S, Fender A. Cis regulation within a cluster of viral microRNAs. Nucleic Acids Res 2021; 49:10018-10033. [PMID: 34417603 PMCID: PMC8464075 DOI: 10.1093/nar/gkab731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although many of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher a regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi's sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor and found that pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs. A mutational analysis showed that, in addition to producing mature miRNAs, they are also important for the optimal expression of the whole set of miRNAs. We showed that this feature depends on the presence of a canonical pre-miRNA at this location since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we exploited this characteristic of the cluster to inhibit the expression of the whole set of miRNAs by targeting the pre-miR-K1 with LNA-based antisense oligonucleotides in cells either expressing a synthetic construct or latently infected with KSHV.
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Affiliation(s)
- Monika Vilimova
- Université de Strasbourg, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée Konrad Roentgen, 67084 Strasbourg, France
| | - Maud Contrant
- Université de Strasbourg, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée Konrad Roentgen, 67084 Strasbourg, France
| | - Ramy Randrianjafy
- Université de Strasbourg, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée Konrad Roentgen, 67084 Strasbourg, France
| | - Philippe Dumas
- Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Department of Integrated structural Biology, 1 rue Laurent Fries, BP10142, 67404 Illkirch-Graffenstaden, France
| | - Endrit Elbasani
- Translational Cancer Medicine Research Program, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland
| | - Päivi M Ojala
- Translational Cancer Medicine Research Program, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland
| | - Sébastien Pfeffer
- Université de Strasbourg, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée Konrad Roentgen, 67084 Strasbourg, France
| | - Aurélie Fender
- Université de Strasbourg, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée Konrad Roentgen, 67084 Strasbourg, France
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27
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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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Lin S, Wang Y, Zhao Z, Wu W, Su Y, Zhang Z, Shen M, Wu P, Qian H, Guo X. Two Putative Cypovirus-Encoded miRNAs Co-regulate the Host Gene of GTP-Binding Nuclear Protein Ran and Facilitate Virus Replication. Front Physiol 2021; 12:663482. [PMID: 34421632 PMCID: PMC8373394 DOI: 10.3389/fphys.2021.663482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 07/13/2021] [Indexed: 01/08/2023] Open
Abstract
microRNA (miRNA) plays important roles in regulating various biological processes, including host-pathogen interaction. Recent studies have demonstrated that virus-encoded miRNAs can manipulate host gene expression to ensure viral effective multiplication. Bombyx mori cypovirus (BmCPV), a double-stranded RNA virus with a segmented genome, is one of the important pathogens for the economically important insect silkworm. Our present study indicated that two putative miRNAs encoded by BmCPV could promote viral replication by inhibiting the gene expression of B. mori GTP-binding nuclear protein Ran (BmRan), an essential component of the exportin-5-mediated nucleocytoplasmic transport of small RNAs. BmCPV-miR-1 and BmCPV-miR-3 are two of the BmCPV-encoded miRNAs identified in our previous studies. BmRan is a common target gene of them with binding sites all located in the 3′-untranslated region (3′-UTR) of its mRNA. The expression levels of the two miRNAs in the midgut of larvae infected with BmCPV gradually increased with the advance of infection, while the expression of the target gene BmRan decreased gradually. The miRNAs and the recombinant target gene consisting of reporter gene mCherry and 3′-UTR of BmRan mRNA were expressed in HEK293T cells for validating the interaction between the miRNAs and the target gene. qRT-PCR results revealed that BmCPV-miR-1 and BmCPV-miR-3 negatively regulate target gene expression not only separately but also cooperatively by binding to the 3′-UTR of BmRan mRNA. By transfecting miRNA mimics into BmN cells and injecting the mimics into the body of silkworm larvae, it was indicated that both BmCPV-miR-1 and BmCPV-miR-3 could repress the expression of BmRan in BmN cells and in the silkworm, and the cooperative action of the two miRNAs could enhance the repression of BmRan expression. Furthermore, the repression of BmRan could facilitate the replication of BmCPV genomic RNAs. It is speculated that BmCPV-miR-1 and BmCPV-miR-3 might reduce the generation of host miRNAs by inhibiting expression of BmRan, thus creating a favorable intracellular environment for virus replication. Our results are helpful to better understand the pathogenic mechanism of BmCPV to the silkworm, and provide insights into one of the evasion strategies used by viruses to counter the host defense for their effective multiplication.
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Affiliation(s)
- Su Lin
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Yongsheng Wang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Ze Zhao
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Wanming Wu
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Yun Su
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Zhendong Zhang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Manman Shen
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Ping Wu
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Heying Qian
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Xijie Guo
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.,Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
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29
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Halim FS, Parmin NA, Hashim U, Gopinath SCB, Dahalan FA, Zakaria II, Ang WC, Jaapar NF. MicroRNA of N-region from SARS-CoV-2: Potential sensing components for biosensor development. Biotechnol Appl Biochem 2021; 69:1696-1711. [PMID: 34378814 PMCID: PMC8427135 DOI: 10.1002/bab.2239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 07/30/2021] [Indexed: 12/29/2022]
Abstract
An oligonucleotide DNA probe has been developed for the application in the DNA electrochemical biosensor for the early diagnosis of coronavirus disease (COVID-19). Here, the virus microRNA from the N-gene of severe acute respiratory syndrome-2 (SARS-CoV-2) was used for the first time as a specific target for detecting the virus and became a framework for developing the complementary DNA probe. The sequence analysis of the virus microRNA was carried out using bioinformatics tools including basic local alignment search tools, multiple sequence alignment from CLUSTLW, microRNA database (miRbase), microRNA target database, and gene analysis. Cross-validation of distinct strains of coronavirus and human microRNA sequences was completed to validate the percentage of identical and consent regions. The percent identity parameter from the bioinformatics tools revealed the virus microRNAs' sequence has a 100% match with the genome of SARS-CoV-2 compared with other coronavirus strains, hence improving the selectivity of the complementary DNA probe. The 30 mer with 53.0% GC content of complementary DNA probe 5' GCC TGA GTT GAG TCA GCA CTG CTC ATG GAT 3' was designed and could be used as a bioreceptor for the biosensor development in the clinical and environmental diagnosis of COVID-19.
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Affiliation(s)
- Fatin Syakirah Halim
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia
| | - N A Parmin
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia
| | - Uda Hashim
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia
| | - Subash C B Gopinath
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia.,Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, 02600, Malaysia
| | - Farrah Aini Dahalan
- Faculty of Civil Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, 02600, Malaysia
| | - Iffah Izzati Zakaria
- Malaysia Genome Institute (MGI), National Institute of Biotechnology (NIBM), Kajang, Selangor, Malaysia
| | - Wei Chern Ang
- Clinical Research Centre, Ministry of Health Malaysia, Hospital Tuanku Fauziah Perlis, Kangar, Perlis, 01000, Malaysia
| | - Nurfareezah Fareezah Jaapar
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia
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30
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Linden G, Janga H, Franz M, Nist A, Stiewe T, Schmeck B, Vázquez O, Schulte LN. Efficient antisense inhibition reveals microRNA-155 to restrain a late-myeloid inflammatory programme in primary human phagocytes. RNA Biol 2021; 18:604-618. [PMID: 33622174 PMCID: PMC8078538 DOI: 10.1080/15476286.2021.1885209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/26/2021] [Accepted: 01/30/2021] [Indexed: 01/05/2023] Open
Abstract
A persisting obstacle in human immunology is that blood-derived leukocytes are notoriously difficult to manipulate at the RNA level. Therefore, our knowledge about immune-regulatory RNA-networks is largely based on tumour cell-line and rodent knockout models, which do not fully mimic human leukocyte biology. Here, we exploit straightforward cell penetrating peptide (CPP) chemistry to enable efficient loss-of-function phenotyping of regulatory RNAs in primary human blood-derived cells. The classical CPP octaarginine (R8) enabled antisense peptide-nucleic-acid (PNA) oligomer delivery into nearly 100% of human blood-derived macrophages without apparent cytotoxicity even up to micromolar concentrations. In a proof-of-principle experiment, we successfully de-repressed the global microRNA-155 regulome in primary human macrophages using a PNA-R8 oligomer, which phenocopies a CRISPR-Cas9 induced gene knockout. Interestingly, although it is often believed that fairly high concentrations (μM) are needed to achieve antisense activity, our PNA-R8 was effective at 200 nM. RNA-seq characterized microRNA-155 as a broad-acting riboregulator, feedback restraining a late myeloid differentiation-induced pro-inflammatory network, comprising MyD88-signalling and ubiquitin-proteasome components. Our results highlight the important role of the microRNA machinery in fine-control of blood-derived human phagocyte immunity and open the door for further studies on regulatory RNAs in difficult-to-transfect primary human immune cells.
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Affiliation(s)
- Greta Linden
- Department of Chemistry, Philipps University Marburg, Marburg, Germany
| | - Harshavardhan Janga
- Department of Medicine, Institute for Lung Research, Philipps University Marburg, Marburg, Germany
| | - Matthias Franz
- Department of Chemistry, Philipps University Marburg, Marburg, Germany
| | - Andrea Nist
- Genomics Core Facility, Philipps University Marburg, Marburg, Germany
| | - Thorsten Stiewe
- Genomics Core Facility, Philipps University Marburg, Marburg, Germany
- Department of Medicine, Institute of Molecular Oncology, Philipps University Marburg, Marburg, Germany
- German Center for Lung Research (DZL), Marburg, Germany
| | - Bernd Schmeck
- Department of Medicine, Institute for Lung Research, Philipps University Marburg, Marburg, Germany
- German Center for Lung Research (DZL), Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Philipps University Marburg, Marburg, Germany
- German Center for Infection Research (DZIF), Marburg, Germany
| | - Olalla Vázquez
- Department of Chemistry, Philipps University Marburg, Marburg, Germany
- Center for Synthetic Microbiology (SYNMIKRO), Philipps University Marburg, Marburg, Germany
| | - Leon N Schulte
- Department of Medicine, Institute for Lung Research, Philipps University Marburg, Marburg, Germany
- German Center for Lung Research (DZL), Marburg, Germany
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31
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Choi YB, Cousins E, Nicholas J. Novel Functions and Virus-Host Interactions Implicated in Pathogenesis and Replication of Human Herpesvirus 8. Recent Results Cancer Res 2021; 217:245-301. [PMID: 33200369 DOI: 10.1007/978-3-030-57362-1_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Human herpesvirus 8 (HHV-8) is classified as a γ2-herpesvirus and is related to Epstein-Barr virus (EBV), a γ1-herpesvirus. One important aspect of the γ-herpesviruses is their association with neoplasia, either naturally or in animal model systems. HHV-8 is associated with B-cell-derived primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), endothelial-derived Kaposi's sarcoma (KS), and KSHV inflammatory cytokine syndrome (KICS). EBV is also associated with a number of B-cell malignancies, such as Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease, in addition to epithelial nasopharyngeal and gastric carcinomas. Despite the similarities between these viruses and their associated malignancies, the particular protein functions and activities involved in key aspects of virus biology and neoplastic transformation appear to be quite distinct. Indeed, HHV-8 specifies a number of proteins for which counterparts had not previously been identified in EBV, other herpesviruses, or even viruses in general, and these proteins are believed to play vital functions in virus biology and to be involved centrally in viral pathogenesis. Additionally, a set of microRNAs encoded by HHV-8 appears to modulate the expression of multiple host proteins to provide conditions conductive to virus persistence within the host and possibly contributing to HHV-8-induced neoplasia. Here, we review the molecular biology underlying these novel virus-host interactions and their potential roles in both virus biology and virus-associated disease.
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Affiliation(s)
- Young Bong Choi
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA.
| | - Emily Cousins
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA
| | - John Nicholas
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD, 21287, USA
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32
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Islam MS, Islam ABMMK. Viral miRNAs confer survival in host cells by targeting apoptosis related host genes. INFORMATICS IN MEDICINE UNLOCKED 2021. [DOI: 10.1016/j.imu.2020.100501] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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33
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Anastasiadou E, Seto AG, Beatty X, Hermreck M, Gilles ME, Stroopinsky D, Pinter-Brown LC, Pestano L, Marchese C, Avigan D, Trivedi P, Escolar DM, Jackson AL, Slack FJ. Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth In Vitro and In Vivo. Clin Cancer Res 2020; 27:1139-1149. [PMID: 33208342 DOI: 10.1158/1078-0432.ccr-20-3139] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/18/2020] [Accepted: 11/13/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. EXPERIMENTAL DESIGN Preclinical studies included the delivery of cobomarsen to highly miR-155-expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. RESULTS Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. CONCLUSIONS Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.
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Affiliation(s)
- Eleni Anastasiadou
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.,Department of Experimental Medicine, Sapienza University of Rome, Italy
| | | | - Xuan Beatty
- miRagen Therapeutics, Inc, Boulder, Colorado
| | | | - Maud-Emmanuelle Gilles
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Dina Stroopinsky
- Department of Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Lauren C Pinter-Brown
- Department of Internal Medicine, Division of Hematology/Oncology, University of California, Irvine, California
| | | | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - David Avigan
- Department of Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Pankaj Trivedi
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | | | | | - Frank J Slack
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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34
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Santpere G, Telford M, Andrés-Benito P, Navarro A, Ferrer I. The Presence of Human Herpesvirus 6 in the Brain in Health and Disease. Biomolecules 2020; 10:E1520. [PMID: 33172107 PMCID: PMC7694807 DOI: 10.3390/biom10111520] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/03/2020] [Accepted: 11/05/2020] [Indexed: 01/03/2023] Open
Abstract
The human herpesvirus 6 (HHV-6) -A and -B are two dsDNA beta-herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV-6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV-6detection in the nervous system. The effort of more than three decades of researching HHV-6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV-6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV-6 in the brains of patients with Alzheimer's disease in light of availableevidence.
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Affiliation(s)
- Gabriel Santpere
- Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), DCEXS, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain
| | - Marco Telford
- Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, 08003 Barcelona, Catalonia, Spain; (M.T.); (A.N.)
| | - Pol Andrés-Benito
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
| | - Arcadi Navarro
- Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, 08003 Barcelona, Catalonia, Spain; (M.T.); (A.N.)
- Catalan Institution of Research and Advanced Studies (ICREA), Passeig de Lluís Companys 23, 08010 Barcelona, Spain
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain
- Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005 Barcelona, Spain
| | - Isidre Ferrer
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
- Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, 08907 Barcelona, Spain
- Bellvitge University Hospital, IDIBELL (Bellvitge Biomedical Research Centre), Hospitalet de Llobregat, 08908 Barcelona, Spain
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The Oncogenic Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of the Tumor-Suppressive miR-15/16 miRNA Family. Cell Rep 2020; 29:2961-2969.e6. [PMID: 31801064 PMCID: PMC6939447 DOI: 10.1016/j.celrep.2019.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/07/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022] Open
Abstract
Many tumor viruses encode oncogenes of cellular origin. Here, we report an oncoviral mimic of a cellular tumor suppressor. The Kaposi’s sarcoma-associated herpesvirus (KSHV) microRNA (miRNA) miR-K6-5p shares sequence similarity to the tumor-suppressive cellular miR-15/16 miRNA family. We show that miR-K6-5p inhibits cell cycle progression, a hallmark function of miR-16. miR-K6-5p regulates conserved miR-15/16 family miRNA targets, including many cell cycle regulators. Inhibition of miR-K6-5p in KSHV-transformed B cells confers a significant growth advantage. Altogether, our data show that KSHV encodes a functional mimic of miR-15/16 family miRNAs. While it is exceedingly well established that oncogenic viruses encode oncogenes of cellular origin, this is an unusual example of an oncogenic virus that encodes a viral mimic of a cellular tumor suppressor. Encoding a tumor-suppressive miRNA could help KSHV balance viral oncogene expression and thereby avoid severe pathogenesis in the healthy host. Morrison et al. report that the tumor virus KSHV encodes a mimic of a cellular tumor suppressor. KSHV miR-K6-5p phenocopies miR-16-induced cell cycle inhibition, shares mRNA targets and binding sites with miR-16, and negatively regulates proliferation in KSHV-infected cells.
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36
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Readhead B, Haure-Mirande JV, Mastroeni D, Audrain M, Fanutza T, Kim SH, Blitzer RD, Gandy S, Dudley JT, Ehrlich ME. miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease. Acta Neuropathol 2020; 140:295-315. [PMID: 32666270 PMCID: PMC8414561 DOI: 10.1007/s00401-020-02185-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/24/2020] [Indexed: 12/19/2022]
Abstract
MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts. In particular, we found that human herpesvirus-6A (HHV-6A) suppressed miR155, recapitulating reports of miR155 inhibition by HHV-6A in infected T-cells, thyrocytes, and natural killer cells. In earlier studies, we also reported the effects of constitutive deletion of miR155 on accelerating the accumulation of Aβ deposits in 4-month-old APP/PSEN1 mice. Herein, we complete the cumulative characterization of transcriptomic, electrophysiological, neuropathological, and learning behavior profiles from 4-, 8- and 10-month-old WT and APP/PSEN1 mice in the absence or presence of miR155. We also integrated human post-mortem brain RNA-sequences from four independent AD consortium studies, together comprising 928 samples collected from six brain regions. We report that gene expression perturbations associated with miR155 deletion in mouse cortex are in aggregate observed to be concordant with AD-associated changes across these independent human late-onset AD (LOAD) data sets, supporting the relevance of our findings to human disease. LOAD has recently been formulated as the clinicopathological manifestation of a multiplex of genetic underpinnings and pathophysiological mechanisms. Our accumulated data are consistent with such a formulation, indicating that miR155 may be uniquely positioned at the intersection of at least four components of this LOAD "multiplex": (1) innate immune response pathways; (2) viral response gene networks; (3) synaptic pathology; and (4) proamyloidogenic pathways involving the amyloid β peptide (Aβ).
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Affiliation(s)
- Ben Readhead
- Arizona State University-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA
- Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | | | - Diego Mastroeni
- Arizona State University-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA
| | - Mickael Audrain
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Tomas Fanutza
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Soong H Kim
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert D Blitzer
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sam Gandy
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Alzheimer's Disease Research Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Mount Sinai Center for Cognitive Health and NFL Neurological Care, Department of Neurology, New York, NY, 10029, USA
- James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY, 10468, USA
| | - Joel T Dudley
- Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Michelle E Ehrlich
- Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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37
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MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma. Cancers (Basel) 2020; 12:cancers12082254. [PMID: 32806571 PMCID: PMC7463991 DOI: 10.3390/cancers12082254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/31/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023] Open
Abstract
Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan–Meier survival analyses (p = 0.027, p = 0.001 and p = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; p = 0.031; RR = 2.59; p = 0.002 and RR = 4.76; p = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment.
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MicroRNAs and Their Targetomes in Tumor-Immune Communication. Cancers (Basel) 2020; 12:cancers12082025. [PMID: 32722019 PMCID: PMC7465095 DOI: 10.3390/cancers12082025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/18/2020] [Accepted: 07/21/2020] [Indexed: 01/14/2023] Open
Abstract
The development of cancer is a complex and dynamically regulated multiple-step process that involves many changes in gene expression. Over the last decade, microRNAs (miRNAs), a class of short regulatory non-coding RNAs, have emerged as key molecular effectors and regulators of tumorigenesis. While aberrant expression of miRNAs or dysregulated miRNA-mediated gene regulation in tumor cells have been shown to be capable of directly promoting or inhibiting tumorigenesis, considering the well-reported role of the immune system in cancer, tumor-derived miRNAs could also impact tumor growth through regulating anti-tumor immune responses. Here, we discuss howmiRNAs can function as central mediators that influence the crosstalk between cancer and the immune system. Moreover, we also review the current progress in the development of novel experimental approaches for miRNA target identification that will facilitate our understanding of miRNA-mediated gene regulation in not only human malignancies, but also in other genetic disorders.
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Guo JY, Wang YS, Chen T, Jiang XX, Wu P, Geng T, Pan ZH, Shang MK, Hou CX, Gao K, Guo XJ. Functional analysis of a miRNA-like small RNA derived from Bombyx mori cytoplasmic polyhedrosis virus. INSECT SCIENCE 2020; 27:449-462. [PMID: 30869181 DOI: 10.1111/1744-7917.12671] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/14/2019] [Accepted: 01/29/2019] [Indexed: 06/09/2023]
Abstract
Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) is a major pathogen of the economic insect silkworm, Bombyx mori. Virus-encoded microRNAs (miRNAs) have been proven to play important roles in host-pathogen interactions. In this study we identified a BmCPV-derived miRNA-like 21 nt small RNA, BmCPV-miR-1, from the small RNA deep sequencing of BmCPV-infected silkworm larvae by stem-loop quantitative real-time PCR (qPCR) and investigated its functions with qPCR and lentiviral expression systems. Bombyx mori inhibitor of apoptosis protein (BmIAP) gene was predicted by both target prediction software miRanda and Targetscan to be one of its target genes with a binding site for BmCPV-miR-1 at the 5' untranslated region. It was found that the expression of BmCPV-miR-1 and its target gene BmIAP were both up-regulated in BmCPV-infected larvae. At the same time, it was confirmed that BmCPV-miR-1 could up-regulate the expression of BmIAP gene in HEK293T cells with lentiviral expression systems and in BmN cells by transfecting mimics. Furthermore, BmCPV-miR-1 mimics could up-regulate the expression level of BmIAP gene in midgut and fat body in the silkworm. In the midgut of BmCPV-infected larvae, BmCPV-miR-1 mimics could be further up-regulated and inhibitors could lower the virus-mediated expression of BmIAP gene. With the viral genomic RNA segments S1 and S10 as indicators, BmCPV-miR-1 mimics could up-regulate and inhibitors down-regulate their replication in the infected silkworm. These results implied that BmCPV-miR-1 could inhibit cell apoptosis in the infected silkworm through up-regulating BmIAP expression, providing the virus with a better cell circumstance for its replication.
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Affiliation(s)
- Jian-Yong Guo
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Yong-Sheng Wang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Tian Chen
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - Xiao-Xu Jiang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - Ping Wu
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Tao Geng
- Environment and Plant Protection Institute, Chinese Academy of Tropical Agricultural Sciences, Haikoou, China
| | - Zhong-Hua Pan
- School of Biology & Basic Medical Science, Soochow University, Suzhou, China
| | - Meng-Ke Shang
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
| | - Cheng-Xiang Hou
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Kun Gao
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
| | - Xi-Jie Guo
- School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, China
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40
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Bermúdez-Barrientos JR, Ramírez-Sánchez O, Chow FWN, Buck AH, Abreu-Goodger C. Disentangling sRNA-Seq data to study RNA communication between species. Nucleic Acids Res 2020; 48:e21. [PMID: 31879784 PMCID: PMC7038986 DOI: 10.1093/nar/gkz1198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 11/23/2019] [Accepted: 12/18/2019] [Indexed: 12/28/2022] Open
Abstract
Many organisms exchange small RNAs (sRNAs) during their interactions, that can target or bolster defense strategies in host-pathogen systems. Current sRNA-Seq technology can determine the sRNAs present in any symbiotic system, but there are very few bioinformatic tools available to interpret the results. We show that one of the biggest challenges comes from sequences that map equally well to the genomes of both interacting organisms. This arises due to the small size of the sRNAs compared to large genomes, and because a large portion of sequenced sRNAs come from genomic regions that encode highly conserved miRNAs, rRNAs or tRNAs. Here, we present strategies to disentangle sRNA-Seq data from samples of communicating organisms, developed using diverse plant and animal species that are known to receive or exchange RNA with their symbionts. We show that sequence assembly, both de novo and genome-guided, can be used for these sRNA-Seq data, greatly reducing the ambiguity of mapping reads. Even confidently mapped sequences can be misleading, so we further demonstrate the use of differential expression strategies to determine true parasite-derived sRNAs within host cells. We validate our methods on new experiments designed to probe the nature of the extracellular vesicle sRNAs from the parasitic nematode Heligmosomoides bakeri that get into mouse intestinal epithelial cells.
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Affiliation(s)
- José Roberto Bermúdez-Barrientos
- Unidad de Genómica Avanzada (Langebio), Centro de Investigación y de Estudios Avanzados del IPN, Irapuato, Guanajuato 36824, México
| | - Obed Ramírez-Sánchez
- Unidad de Genómica Avanzada (Langebio), Centro de Investigación y de Estudios Avanzados del IPN, Irapuato, Guanajuato 36824, México
| | - Franklin Wang-Ngai Chow
- Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3JT, UK
| | - Amy H Buck
- Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3JT, UK
| | - Cei Abreu-Goodger
- Unidad de Genómica Avanzada (Langebio), Centro de Investigación y de Estudios Avanzados del IPN, Irapuato, Guanajuato 36824, México
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Fröhlich J, Grundhoff A. Epigenetic control in Kaposi sarcoma-associated herpesvirus infection and associated disease. Semin Immunopathol 2020; 42:143-157. [PMID: 32219477 PMCID: PMC7174275 DOI: 10.1007/s00281-020-00787-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 01/20/2020] [Indexed: 12/15/2022]
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies of endothelial and B-cell origin. The fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of KSHV-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. Heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. Since KSHV encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of KSHV-associated tumors. The fact that heritable histone modifications have also been shown to regulate viral gene expression programs in KSHV-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. We here review what is presently known about the role of epigenetic regulation of viral and host chromatin in KSHV infection and discuss how viral manipulation of these processes may contribute to the development of KSHV-associated disease.
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Affiliation(s)
- Jacqueline Fröhlich
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Adam Grundhoff
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
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42
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Ruiz-Tagle C, Naves R, Balcells ME. Unraveling the Role of MicroRNAs in Mycobacterium tuberculosis Infection and Disease: Advances and Pitfalls. Infect Immun 2020; 88:e00649-19. [PMID: 31871103 PMCID: PMC7035921 DOI: 10.1128/iai.00649-19] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Tuberculosis (TB) is an infectious disease of extremely high epidemiological burden worldwide that is easily acquired through the inhalation of infected respiratory droplets. The complex pathogenesis of this infection spans from subjects never developing this disease despite intense exposure, to others in which immune containment fails catastrophically and severe or disseminated forms of disease ensue. In recent decades, microRNAs (miRNAs) have gained increasing attention due to their role as gene silencers and because of their altered expression in diverse human diseases, including some infections. Recent research regarding miRNAs and TB has revealed that the expression profile for particular miRNAs clearly changes upon Mycobacterium tuberculosis infection and also varies in the different stages of this disease. However, despite the growing number of studies-some of which have even proposed some miRNAs as potential biomarkers-methodological variations and key differences in relevant factors, such as sex and age, cell type analyzed, M. tuberculosis strain, and antimicrobial therapy status, strongly hinder the comparison of data. In this review, we summarize and discuss the literature and highlight the role of selected miRNAs that have specifically and more consistently been associated with M. tuberculosis infection, together with a discussion of the possible gene and immune regulation pathways involved.
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Affiliation(s)
- Cinthya Ruiz-Tagle
- Departamento de Enfermedades Infecciosas del Adulto, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Naves
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - María Elvira Balcells
- Departamento de Enfermedades Infecciosas del Adulto, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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43
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Weidner-Glunde M, Kruminis-Kaszkiel E, Savanagouder M. Herpesviral Latency-Common Themes. Pathogens 2020; 9:E125. [PMID: 32075270 PMCID: PMC7167855 DOI: 10.3390/pathogens9020125] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 12/14/2022] Open
Abstract
Latency establishment is the hallmark feature of herpesviruses, a group of viruses, of which nine are known to infect humans. They have co-evolved alongside their hosts, and mastered manipulation of cellular pathways and tweaking various processes to their advantage. As a result, they are very well adapted to persistence. The members of the three subfamilies belonging to the family Herpesviridae differ with regard to cell tropism, target cells for the latent reservoir, and characteristics of the infection. The mechanisms governing the latent state also seem quite different. Our knowledge about latency is most complete for the gammaherpesviruses due to previously missing adequate latency models for the alpha and beta-herpesviruses. Nevertheless, with advances in cell biology and the availability of appropriate cell-culture and animal models, the common features of the latency in the different subfamilies began to emerge. Three criteria have been set forth to define latency and differentiate it from persistent or abortive infection: 1) persistence of the viral genome, 2) limited viral gene expression with no viral particle production, and 3) the ability to reactivate to a lytic cycle. This review discusses these criteria for each of the subfamilies and highlights the common strategies adopted by herpesviruses to establish latency.
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Affiliation(s)
- Magdalena Weidner-Glunde
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima Str. 10, 10-748 Olsztyn, Poland; (E.K.-K.); (M.S.)
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44
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Gallo A, Miceli V, Bulati M, Iannolo G, Contino F, Conaldi PG. Viral miRNAs as Active Players and Participants in Tumorigenesis. Cancers (Basel) 2020; 12:358. [PMID: 32033193 PMCID: PMC7072176 DOI: 10.3390/cancers12020358] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/22/2020] [Accepted: 01/31/2020] [Indexed: 02/07/2023] Open
Abstract
The theory that viruses play a role in human cancers is now supported by scientific evidence. In fact, around 12% of human cancers, a leading cause of morbidity and mortality in some regions, are attributed to viral infections. However, the molecular mechanism remains complex to decipher. In recent decades, the uncovering of cellular miRNAs, with their invaluable potential as diagnostic and prognostic biomarkers, has increased the number of studies being conducted regarding human cancer diagnosis. Viruses develop clever mechanisms to succeed in the maintenance of the viral life cycle, and some viruses, especially herpesviruses, encode for miRNA, v-miRNAs. Through this viral miRNA, the viruses are able to manipulate cellular and viral gene expression, driving carcinogenesis and escaping the host innate or adaptive immune system. In this review, we have discussed the main viral miRNAs and virally influenced cellular pathways, and their capability to drive carcinogenesis.
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Affiliation(s)
- Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Flavia Contino
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
- Scienze Mediche Chirurgiche E Sperimentali, Università degli Studi di Sassari, Piazza Universita, 07100 Sassari, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
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45
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Ju E, Li T, Liu Z, da Silva SR, Wei S, Zhang X, Wang X, Gao SJ. Specific Inhibition of Viral MicroRNAs by Carbon Dots-Mediated Delivery of Locked Nucleic Acids for Therapy of Virus-Induced Cancer. ACS NANO 2020; 14:476-487. [PMID: 31895530 PMCID: PMC7119180 DOI: 10.1021/acsnano.9b06333] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Viruses are associated with up to 15% of human cancer. MicroRNAs (miRNAs) encoded by numerous oncogenic viruses including Kaposi's sarcoma-associated herpesvirus (KSHV) play significant roles in regulating the proliferation and survival of virus-induced cancer cells, hence representing attractive therapeutic targets. Here, we report that specific inhibition of viral miRNAs by carbon dots (Cdots)-mediated delivery of locked nucleic acid (LNA)-based suppressors inhibit the proliferation of KSHV-associated primary effusion lymphoma (PEL) cells. Specifically, a combination of Cdots-LNAs to knock down the levels of KSHV miR-K12-1, miR-K12-4, and miR-K12-11 induces apoptosis and inhibits proliferation of PEL cells. Significantly, these Cdots-LNAs effectively inhibit the initiation of PEL and regress established PEL in a xenograft mouse model. These results demonstrate the feasibility of using Cdots to deliver miRNA suppressors for targeting viral cancers. Our study with viral miRNAs as targets may provide the scientific basis for using antisense drugs for human cancers associated with oncogenic viruses.
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MESH Headings
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Carbon/chemistry
- Cell Proliferation/drug effects
- Cells, Cultured
- Drug Screening Assays, Antitumor
- Female
- Herpesvirus 8, Human/chemistry
- Lymphoma/drug therapy
- Lymphoma/pathology
- Lymphoma/virology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, SCID
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/virology
- Oligonucleotides/chemistry
- Oligonucleotides/pharmacology
- Particle Size
- Quantum Dots/chemistry
- RNA, Viral/antagonists & inhibitors
- Rats
- Surface Properties
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Affiliation(s)
- Enguo Ju
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Tingting Li
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Zhen Liu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering , Beijing University of Chemical Technology , Beijing 100029 , People's Republic of China
| | - Suzane Ramos da Silva
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Shan Wei
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Xinquan Zhang
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Xian Wang
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
| | - Shou-Jiang Gao
- Cancer Virology Program, UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics , University of Pittsburgh , Pittsburgh , Pennsylvania 15232 , United States
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46
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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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47
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Murmann AE, Bartom ET, Schipma MJ, Vilker J, Chen S, Peter ME. 6mer Seed Toxicity in Viral microRNAs. iScience 2019; 23:100737. [PMID: 31838022 PMCID: PMC7033618 DOI: 10.1016/j.isci.2019.11.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 11/13/2019] [Accepted: 11/15/2019] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are short double-stranded noncoding RNAs (19-23 nucleotides) that regulate gene expression by suppressing mRNAs through RNA interference. Targeting is determined by the seed sequence (position 2-7/8) of the mature miRNA. A minimal G-rich seed of just six nucleotides is highly toxic to cells by targeting genes essential for cell survival. A screen of 215 miRNAs encoded by 17 human pathogenic viruses (v-miRNAs) now suggests that a number of v-miRNAs can kill cells through a G-rich 6mer sequence embedded in their seed. Specifically, we demonstrate that miR-K12-6-5p, an oncoviral mimic of the tumor suppressive miR-15/16 family encoded by human Kaposi sarcoma-associated herpes virus, harbors a noncanonical toxic 6mer seed (position 3-8) and that v-miRNAs are more likely than cellular miRNAs to utilize a noncanonical 6mer seed. Our data suggest that during evolution viruses evolved to use 6mer seed toxicity to kill cells.
Tumor suppressive miR-15/16-5p with a toxic 6mer seed targets survival genes kshv-miR-K12-6-5p, a paralog of hsa-miR-15/16-5p carries an offset toxic 6mer seed A screen of 215 viral miRNAs identifies miRNAs that contain a toxic 6mer seed Many human viral miRNAs have the capacity to kill through 6mer seed toxicity
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Affiliation(s)
- Andrea E Murmann
- Division Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Elizabeth T Bartom
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611, USA
| | - Matthew J Schipma
- Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611, USA
| | - Jacob Vilker
- Division Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Siquan Chen
- Cellular Screening Center, Institute for Genomics & Systems Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Marcus E Peter
- Division Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611, USA.
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48
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Kang Q, Zhang X, Cao N, Chen C, Yi J, Hao L, Ji Y, Liu X, Lu J. EGCG enhances cancer cells sensitivity under 60Coγ radiation based on miR-34a/Sirt1/p53. Food Chem Toxicol 2019; 133:110807. [DOI: 10.1016/j.fct.2019.110807] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/01/2019] [Accepted: 09/05/2019] [Indexed: 01/04/2023]
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49
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Liu TY, Zhang YC, Lin YQ, Hu YF, Zhang Y, Wang D, Wang Y, Ning L. Exploration of invasive mechanisms via global ncRNA-associated virus-host crosstalk. Genomics 2019; 112:1643-1650. [PMID: 31626899 DOI: 10.1016/j.ygeno.2019.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/23/2019] [Accepted: 10/07/2019] [Indexed: 12/21/2022]
Abstract
Viral infection is a complex pathogenesis and the underlying molecular mechanisms remain poorly understood. In this study, an integrated multiple resources analysis was performed and showed that the cellular ncRNAs and proteins targeted by viruses were primarily "hubs" and "bottlenecks" in the human ncRNA/protein-protein interaction. The common proteins targeted by both viral ncRNAs and proteins tended to skew toward higher degrees and betweenness compared with other proteins, showed significant enrichment in the cell death process. Specifically, >800 pairs of human cellular ncRNAs and viral ncRNAs that exhibited a high degree of functional homology were identified, representing potential ncRNA-mediated co-regulation patterns of viral invasion. Additionally, clustering analysis further revealed several distinct viral clusters with obvious functional divergence. Overall, this is the first attempt to systematically explore the invasive mechanism via global ncRNA-associated virus-host crosstalk. Our results provide useful information in comprehensively understanding the viral invasive mechanism.
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Affiliation(s)
- Tian-Yuan Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Yun-Cong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Yun-Qing Lin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
| | - Yong-Fei Hu
- Dermatology Hospital, Southern Medical University, Guangzhou 510091, China
| | - Yang Zhang
- Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan 528308, China
| | - Dong Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
| | - Yan Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Lin Ning
- Dermatology Hospital, Southern Medical University, Guangzhou 510091, China.
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Chen X, Xie D, Zhao Q, You ZH. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform 2019; 20:515-539. [PMID: 29045685 DOI: 10.1093/bib/bbx130] [Citation(s) in RCA: 423] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/13/2017] [Indexed: 12/22/2022] Open
Abstract
Plenty of microRNAs (miRNAs) were discovered at a rapid pace in plants, green algae, viruses and animals. As one of the most important components in the cell, miRNAs play a growing important role in various essential and important biological processes. For the recent few decades, amounts of experimental methods and computational models have been designed and implemented to identify novel miRNA-disease associations. In this review, the functions of miRNAs, miRNA-target interactions, miRNA-disease associations and some important publicly available miRNA-related databases were discussed in detail. Specially, considering the important fact that an increasing number of miRNA-disease associations have been experimentally confirmed, we selected five important miRNA-related human diseases and five crucial disease-related miRNAs and provided corresponding introductions. Identifying disease-related miRNAs has become an important goal of biomedical research, which will accelerate the understanding of disease pathogenesis at the molecular level and molecular tools design for disease diagnosis, treatment and prevention. Computational models have become an important means for novel miRNA-disease association identification, which could select the most promising miRNA-disease pairs for experimental validation and significantly reduce the time and cost of the biological experiments. Here, we reviewed 20 state-of-the-art computational models of predicting miRNA-disease associations from different perspectives. Finally, we summarized four important factors for the difficulties of predicting potential disease-related miRNAs, the framework of constructing powerful computational models to predict potential miRNA-disease associations including five feasible and important research schemas, and future directions for further development of computational models.
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Affiliation(s)
- Xing Chen
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China
| | - Di Xie
- School of Mathematics, Liaoning University
| | - Qi Zhao
- School of Mathematics, Liaoning University
| | - Zhu-Hong You
- Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Science
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