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Milcamps R, Michiels T. Involvement of paraspeckle components in viral infections. Nucleus 2024; 15:2350178. [PMID: 38717150 PMCID: PMC11086011 DOI: 10.1080/19491034.2024.2350178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/22/2024] [Indexed: 05/12/2024] Open
Abstract
Paraspeckles are non-membranous subnuclear bodies, formed through the interaction between the architectural long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) and specific RNA-binding proteins, including the three Drosophila Behavior/Human Splicing (DBHS) family members (PSPC1 (Paraspeckle Component 1), SFPQ (Splicing Factor Proline and Glutamine Rich) and NONO (Non-POU domain-containing octamer-binding protein)). Paraspeckle components were found to impact viral infections through various mechanisms, such as induction of antiviral gene expression, IRES-mediated translation, or viral mRNA polyadenylation. A complex involving NEAT1 RNA and paraspeckle proteins was also found to modulate interferon gene transcription after nuclear DNA sensing, through the activation of the cGAS-STING axis. This review aims to provide an overview on how these elements actively contribute to the dynamics of viral infections.
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Affiliation(s)
- Romane Milcamps
- Université catholique de Louvain, de Duve Institute, Brussels, Belgium
| | - Thomas Michiels
- Université catholique de Louvain, de Duve Institute, Brussels, Belgium
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2
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Madhry D, Kumari K, Meena V, Roy R, Verma B. Unravelling tRNA fragments in DENV pathogenesis: Insights from RNA sequencing. Sci Rep 2024; 14:18357. [PMID: 39112524 PMCID: PMC11306563 DOI: 10.1038/s41598-024-69391-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 08/05/2024] [Indexed: 08/10/2024] Open
Abstract
Small non-coding RNAs (sncRNAs) derived from tRNAs are known as tRNA-derived small RNAs (tsRNAs). These tsRNAs are further categorized into tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), which play significant roles in the various molecular mechanisms underlying certain human diseases. However, the generation of tsRNAs and their potential roles during Dengue virus (DENV) infection is not yet known. Here, we performed small RNA sequencing to identify the generation and alterations in tsRNAs expression profiles of DENV-infected Huh7 cells. Upon DENV infection, tRNA fragmentation was found to be increased. We identified a significant number of differentially expressed tsRNAs during DENV infection. Interestingly, the 3'tRF population showed upregulation, while the i-tRF population exhibited downregulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to analyze the impact of differentially expressed tsRNAs on DENV pathogenesis. Our results suggest that differentially expressed tsRNAs are involved in transcriptional regulation via RNA polymerase II promoter and metabolic pathways. Overall, our study contributes significantly to our understanding of the roles played by tsRNAs in the complex dynamics of DENV infection.
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Affiliation(s)
- Deeksha Madhry
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Kiran Kumari
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Varsha Meena
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Riya Roy
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Bhupendra Verma
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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3
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Bermudez-Santana CI, Gallego-Gómez JC. Toward a Categorization of Virus-ncRNA Interactions in the World of RNA to Disentangle the Tiny Secrets of Dengue Virus. Viruses 2024; 16:804. [PMID: 38793685 PMCID: PMC11125801 DOI: 10.3390/v16050804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
In recent years, the function of noncoding RNAs (ncRNAs) as regulatory molecules of cell physiology has begun to be better understood. Advances in viral molecular biology have shown that host ncRNAs, cellular factors, and virus-derived ncRNAs and their interplay are strongly disturbed during viral infections. Nevertheless, the folding of RNA virus genomes has also been identified as a critical factor in regulating canonical and non-canonical functions. Due to the influence of host ncRNAs and the structure of RNA viral genomes, complex molecular and cellular processes in infections are modulated. We propose three main categories to organize the current information about RNA-RNA interactions in some well-known human viruses. The first category shows examples of host ncRNAs associated with the immune response triggered in viral infections. Even though miRNAs introduce a standpoint, they are briefly presented to keep researchers moving forward in uncovering other RNAs. The second category outlines interactions between virus-host ncRNAs, while the third describes how the structure of the RNA viral genome serves as a scaffold for processing virus-derived RNAs. Our grouping may provide a comprehensive framework to classify ncRNA-host-cell interactions for emerging viruses and diseases. In this sense, we introduced them to organize DENV-host-cell interactions.
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Affiliation(s)
- Clara Isabel Bermudez-Santana
- Computational and theoretical RNomics Group, Center of Excellence in Scientific Computing, Universidad Nacional de Colombia, Bogotá 111321, Colombia
| | - Juan Carlos Gallego-Gómez
- Grupo de Medicina de Traslación, Facultad de Medicina, Universidad de Antioquia, Medellín 050010, Colombia;
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Ajmeriya S, Bharti DR, Kumar A, Rana S, Singh H, Karmakar S. In silico approach for the identification of tRNA-derived small non-coding RNAs in SARS-CoV infection. J Appl Genet 2024; 65:403-413. [PMID: 38514586 DOI: 10.1007/s13353-024-00853-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/12/2024] [Accepted: 02/29/2024] [Indexed: 03/23/2024]
Abstract
tsRNAs (tRNA-derived small non-coding RNAs), including tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been implicated in some viral infections, such as respiratory viral infections. However, their involvement in SARS-CoV infection is completely unknown. A comprehensive analysis was performed to determine tsRNA populations in a mouse model of SARS-CoV-infected samples containing the wild-type and attenuated viruses. Data from the Gene Expression Omnibus (GEO) dataset at NCBI (accession ID GSE90624 ) was used for this study. A count matrix was generated for the tRNAs. Differentially expressed tRNAs, followed by tsRNAs derived from each significant tRNAs at different conditions and time points between the two groups WT(SARS-CoV-MA15-WT) vs Mock and ΔE (SARS-CoV-MA15-ΔE) vs Mock were identified. Notably, significantly differentially expressed tRNAs at 2dpi but not at 4dpi. The tsRNAs originating from differentially expressed tRNAs across all the samples belonging to each condition (WT, ΔE, and Mock) were identified. Intriguingly, tRFs (tRNA-derived RNA fragments) exhibited higher levels compared to tiRNAs (tRNA-derived stress-induced RNAs) across all samples associated with WT SARS-CoV strain compared to ΔE and mock-infected samples. This discrepancy suggests a non-random formation of tsRNAs, hinting at a possible involvement of tsRNAs in SARS-CoV viral infection.
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Affiliation(s)
- Swati Ajmeriya
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Deepak Ramkumar Bharti
- Trinity Translation Medicine Institute, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Amit Kumar
- ICMR-AIIMS Computational Genomics Center, Division of Biomedical Informatics, Division, Indian Council of Medical Research, Ansari Nagar, New Delhi, India
| | - Shweta Rana
- ICMR-AIIMS Computational Genomics Center, Division of Biomedical Informatics, Division, Indian Council of Medical Research, Ansari Nagar, New Delhi, India
| | - Harpreet Singh
- ICMR-AIIMS Computational Genomics Center, Division of Biomedical Informatics, Division, Indian Council of Medical Research, Ansari Nagar, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
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5
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Mohanty P, Panda P, Acharya RK, Pande B, Bhaskar LVKS, Verma HK. Emerging perspectives on RNA virus-mediated infections: from pathogenesis to therapeutic interventions. World J Virol 2023; 12:242-255. [PMID: 38187500 PMCID: PMC10768389 DOI: 10.5501/wjv.v12.i5.242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/07/2023] [Accepted: 11/29/2023] [Indexed: 12/25/2023] Open
Abstract
RNA viruses continue to pose significant threats to global public health, necessitating a profound understanding of their pathogenic mechanisms and the development of effective therapeutic interventions. This manuscript provides a comprehensive overview of emerging perspectives on RNA virus-mediated infections, spanning from the intricate intricacies of viral pathogenesis to the forefront of innovative therapeutic strategies. A critical exploration of antiviral drugs sets the stage, highlighting the diverse classes of compounds that target various stages of the viral life cycle, underscoring the ongoing efforts to combat viral infections. Central to this discussion is the exploration of RNA-based therapeutics, with a spotlight on messenger RNA (mRNA)-based approaches that have revolutionized the landscape of antiviral interventions. Furthermore, the manuscript delves into the intricate world of delivery systems, exploring inno-vative technologies designed to enhance the efficiency and safety of mRNA vaccines. By analyzing the challenges and advancements in delivery mechanisms, this review offers a roadmap for future research and development in this critical area. Beyond conventional infectious diseases, the document explores the expanding applications of mRNA vaccines, including their promising roles in cancer immunotherapy and personalized medicine approaches. This manuscript serves as a valuable resource for researchers, clinicians, and policymakers alike, offering a nuanced perspective on RNA virus pathogenesis and the cutting-edge therapeutic interventions. By synthesizing the latest advancements and challenges, this review contributes significantly to the ongoing discourse in the field, driving the development of novel strategies to combat RNA virus-mediated infections effectively.
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Affiliation(s)
- Pratik Mohanty
- Department of Bioscience and Bioengineering, Indian Institute of Technology, Guwahati 781039, Assam, India
| | - Poojarani Panda
- Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Rakesh Kumar Acharya
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Bilaspur 495009, Chhattisgarh, India
| | - Babita Pande
- Department of Physiology, All India Institute of Medical Science, Raipur 492001, chhattisgarh, India
| | - LVKS Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Bilaspur 495009, Chhattisgarh, India
| | - Henu Kumar Verma
- Lung Health and Immunity, Helmholtz Zentrum Munich, Munich 85764, Bayren, Germany
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Arora H, Prajapati B, Seth P. Potential role of lncRNA in impairing cellular properties of human neural progenitor cells following exposure to Zika virus E protein. Exp Neurol 2023; 368:114493. [PMID: 37479020 DOI: 10.1016/j.expneurol.2023.114493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/08/2023] [Accepted: 07/18/2023] [Indexed: 07/23/2023]
Abstract
Zika virus (ZIKV) infection during the first trimester of the pregnancy may lead to Congenital zika syndrome in the neonates. The viral infection hampers foetal brain development and causes microcephaly. Human neural progenitor cells (hNPCs) play an important role in brain development, however they are highly susceptible to ZIKV infection. In this study, we elucidated the molecular mechanisms that lead to cellular alterations in hNPCs due to ZIKV E-protein. We investigated proliferation, differentiation, migration and inflammation in hNPCs, which may lead to microcephaly. In our study, we found that ZIKV E-protein causes cell cycle arrest, decrease in proliferation and increase in mitotic length of the dividing hNPCs. We observed CyclinD1 and upstream molecules (p21 and p53) of the pathway are dysregulated, and intracellular calcium at basal level as well as upon ATP stimulation were reduced following over expression of ZIKV E-protein. ZIKV E-protein transfected hNPCs exhibited pre-mature differentiation with pro-neural genes upregulated. Furthermore, ZIKV E-protein disrupted migrational properties of hNPCs and caused elevated levels of inflammatory chemokines and cytokines. To gain insights into molecular mechanisms of these effects on hNPCs, we explored the possible involvement of long non coding RNAs in ZIKV neuropathogenesis. We have shortlisted lncRNAs associated with differentially expressed genes from publicly available transcriptomic data and found some of those lncRNAs are differentially expressed upon E-protein transfection of hNPCs. Gene ontology analysis suggest these lncRNAs play an important role in regulation of viral life cycle, host's defence response and cell proliferation.
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Affiliation(s)
- Himali Arora
- Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurugram, Haryana, India
| | - Bharat Prajapati
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden
| | - Pankaj Seth
- Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurugram, Haryana, India.
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Lin Y, Sun Q, Zhang B, Zhao W, Shen C. The regulation of lncRNAs and miRNAs in SARS-CoV-2 infection. Front Cell Dev Biol 2023; 11:1229393. [PMID: 37576600 PMCID: PMC10416254 DOI: 10.3389/fcell.2023.1229393] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/20/2023] [Indexed: 08/15/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) was a global endemic that continues to cause a large number of severe illnesses and fatalities. There is increasing evidence that non-coding RNAs (ncRNAs) are crucial regulators of viral infection and antiviral immune response and the role of non-coding RNAs in SARS-CoV-2 infection has now become the focus of scholarly inquiry. After SARS-CoV-2 infection, some ncRNAs' expression levels are regulated to indirectly control the expression of antiviral genes and viral gene replication. However, some other ncRNAs are hijacked by SARS-CoV-2 in order to help the virus evade the immune system by suppressing the expression of type I interferon (IFN-1) and controlling cytokine levels. In this review, we summarize the recent findings of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) among non-coding RNAs in SARS-CoV-2 infection and antiviral response, discuss the potential mechanisms of actions, and prospects for the detection, treatment, prevention and future directions of SARS-CoV-2 infection research.
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Affiliation(s)
| | | | | | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chenguang Shen
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Fossat N, Lundsgaard EA, Costa R, Rivera-Rangel LR, Nielsen L, Mikkelsen LS, Ramirez S, Bukh J, Scheel TKH. Identification of the viral and cellular microRNA interactomes during SARS-CoV-2 infection. Cell Rep 2023; 42:112282. [PMID: 36961814 PMCID: PMC9995319 DOI: 10.1016/j.celrep.2023.112282] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 01/24/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had a tremendous impact worldwide. Mapping virus-host interactions is critical to understand disease progression. MicroRNAs (miRNAs) are important RNA regulators, but their interaction with SARS-CoV-2 RNA was not experimentally investigated. Here, using Argonaute (AGO) cross-linking immunoprecipitation combined with RNA proximity ligation (CLEAR-CLIP), we provide unbiased mapping of SARS-CoV-2/miRNA interactions. We identified six main regions on the viral RNA bound primarily by one specific miRNA. Targeted mutagenesis and AGO1-3 knockdown demonstrated that these interactions are not critical for virus production. Moreover, we identified perturbed regulation of cellular miRNA interactions during infection, including non-compensated viral sequestration of the miR-15 family. Transcriptome analysis further showed that mRNAs targeted by this miRNA family are derepressed. This work delineates the interphase between miRNA regulation and SARS-CoV-2 infection and further contributes to deciphering the full molecular interactome of this virus.
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Affiliation(s)
- Nicolas Fossat
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Emma A Lundsgaard
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Rui Costa
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lizandro R Rivera-Rangel
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Louise Nielsen
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lotte S Mikkelsen
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Santseharay Ramirez
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Troels K H Scheel
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, 10065 NY, USA.
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Girardi E, Messmer M, Lopez P, Fender A, Chicher J, Chane-Woon-Ming B, Hammann P, Pfeffer S. Proteomics-based determination of double-stranded RNA interactome reveals known and new factors involved in Sindbis virus infection. RNA (NEW YORK, N.Y.) 2023; 29:361-375. [PMID: 36617674 PMCID: PMC9945444 DOI: 10.1261/rna.079270.122] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 12/15/2022] [Indexed: 06/17/2023]
Abstract
Viruses are obligate intracellular parasites, which depend on the host cellular machineries to replicate their genome and complete their infectious cycle. Long double-stranded (ds)RNA is a common viral by-product originating during RNA virus replication and is universally sensed as a danger signal to trigger the antiviral response. As a result, viruses hide dsRNA intermediates into viral replication factories and have evolved strategies to hijack cellular proteins for their benefit. The characterization of the host factors associated with viral dsRNA and involved in viral replication remains a major challenge to develop new antiviral drugs against RNA viruses. Here, we performed anti-dsRNA immunoprecipitation followed by mass spectrometry analysis to fully characterize the dsRNA interactome in Sindbis virus (SINV) infected human cells. Among the identified proteins, we characterized SFPQ (splicing factor, proline-glutamine rich) as a new dsRNA-associated proviral factor upon SINV infection. We showed that SFPQ depletion reduces SINV infection in human HCT116 and SK-N-BE(2) cells, suggesting that SFPQ enhances viral production. We demonstrated that the cytoplasmic fraction of SFPQ partially colocalizes with dsRNA upon SINV infection. In agreement, we proved by RNA-IP that SFPQ can bind dsRNA and viral RNA. Furthermore, we showed that overexpression of a wild-type, but not an RNA binding mutant SFPQ, increased viral infection, suggesting that RNA binding is essential for its positive effect on the virus. Overall, this study provides the community with a compendium of dsRNA-associated factors during viral infection and identifies SFPQ as a new proviral dsRNA binding protein.
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Affiliation(s)
- Erika Girardi
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
| | - Mélanie Messmer
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
| | - Paula Lopez
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
| | - Aurélie Fender
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
| | - Johana Chicher
- Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire du CNRS, Plateforme Protéomique Strasbourg-Esplanade, 67084 Strasbourg France
| | - Béatrice Chane-Woon-Ming
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
| | - Philippe Hammann
- Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire du CNRS, Plateforme Protéomique Strasbourg-Esplanade, 67084 Strasbourg France
| | - Sébastien Pfeffer
- Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 67084 Strasbourg France
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Lee CY, Nguyen AT, Doan LH, Chu LW, Chang CH, Liu HK, Lee IL, Wang TH, Lai JM, Tsao SM, Liao HJ, Ping YH, Huang CYF. Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects. Viruses 2023; 15:641. [PMID: 36992350 PMCID: PMC10054482 DOI: 10.3390/v15030641] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/05/2023] [Accepted: 02/23/2023] [Indexed: 03/04/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.
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Affiliation(s)
- Chia-Yin Lee
- Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan
| | - Anh Thuc Nguyen
- Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan
| | - Ly Hien Doan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Li-Wei Chu
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan
| | - Hui-Kang Liu
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine (NRICM), Ministry of Health and Welfare, Taipei 112304, Taiwan
| | - I-Lin Lee
- PhytoHeath Corporation, Taipei 105403, Taiwan
| | | | - Jin-Mei Lai
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Shih-Ming Tsao
- Division of Pulmonary Medicine, School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 402306, Taiwan
| | - Hsiu-Jung Liao
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan
| | - Yueh-Hsin Ping
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
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11
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Zhang K, Lee YS, Lee I, Bao X. Editorial: Small non-coding RNAs in diseases. Front Mol Biosci 2023; 9:1086768. [PMID: 36660424 PMCID: PMC9846153 DOI: 10.3389/fmolb.2022.1086768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/30/2022] [Indexed: 01/05/2023] Open
Affiliation(s)
- Ke Zhang
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States
| | - Yong Sun Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, South Korea
| | - Inhan Lee
- miRcore, Ann Arbor, MI, United States
| | - Xiaoyong Bao
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States,Institute for Translational Science, University of Texas Medical Branch, Galveston, TX, United States,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States,*Correspondence: Xiaoyong Bao,
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12
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Venkatesan A, Barik A, Paul D, Muthaiyan M, Das R. Identification of novel lncRNA by reanalysis of RNA-seq data in Zika Virus Infected hiNPCs. Virusdisease 2022; 33:185-193. [DOI: 10.1007/s13337-022-00771-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 06/03/2022] [Indexed: 11/29/2022] Open
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Ward B, Yombi JC, Balligand JL, Cani PD, Collet JF, de Greef J, Dewulf JP, Gatto L, Haufroid V, Jodogne S, Kabamba B, Pyr dit Ruys S, Vertommen D, Elens L, Belkhir L. HYGIEIA: HYpothesizing the Genesis of Infectious Diseases and Epidemics through an Integrated Systems Biology Approach. Viruses 2022; 14:1373. [PMID: 35891354 PMCID: PMC9318602 DOI: 10.3390/v14071373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 12/13/2022] Open
Abstract
More than two years on, the COVID-19 pandemic continues to wreak havoc around the world and has battle-tested the pandemic-situation responses of all major global governments. Two key areas of investigation that are still unclear are: the molecular mechanisms that lead to heterogenic patient outcomes, and the causes of Post COVID condition (AKA Long-COVID). In this paper, we introduce the HYGIEIA project, designed to respond to the enormous challenges of the COVID-19 pandemic through a multi-omic approach supported by network medicine. It is hoped that in addition to investigating COVID-19, the logistics deployed within this project will be applicable to other infectious agents, pandemic-type situations, and also other complex, non-infectious diseases. Here, we first look at previous research into COVID-19 in the context of the proteome, metabolome, transcriptome, microbiome, host genome, and viral genome. We then discuss a proposed methodology for a large-scale multi-omic longitudinal study to investigate the aforementioned biological strata through high-throughput sequencing (HTS) and mass-spectrometry (MS) technologies. Lastly, we discuss how a network medicine approach can be used to analyze the data and make meaningful discoveries, with the final aim being the translation of these discoveries into the clinics to improve patient care.
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Affiliation(s)
- Bradley Ward
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics Group (PMGK), Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (B.W.); (S.P.d.R.)
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
| | - Jean Cyr Yombi
- Department of Internal Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Jean-Luc Balligand
- WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Experimentale et Clinique (IREC), Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Patrice D. Cani
- WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Jean-François Collet
- WELBIO (Walloon Excellence in Life Sciences and Biotechnology), de Duve Institute, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Julien de Greef
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
- Department of Internal Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Joseph P. Dewulf
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
- Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Department of Biochemistry, de Duve Institute, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Laurent Gatto
- Computational Biology and Bioinformatics Unit (CBIO), de Duve Institute, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Vincent Haufroid
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
- Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Sébastien Jodogne
- Computer Science and Engineering Department (INGI), Institute of Information and Communication Technologies, Electronics and Applied Mathematics (ICTEAM), UCLouvain, Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium;
| | - Benoît Kabamba
- Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Pôle de Microbiologie, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Sébastien Pyr dit Ruys
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics Group (PMGK), Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (B.W.); (S.P.d.R.)
| | - Didier Vertommen
- De Duve Institute, and MASSPROT Platform, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenomics and Pharmacokinetics Group (PMGK), Louvain Drug Research Institute (LDRI), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (B.W.); (S.P.d.R.)
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
| | - Leïla Belkhir
- Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (J.d.G.); (J.P.D.); (V.H.)
- Department of Internal Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
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14
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Fishburn AT, Pham OH, Kenaston MW, Beesabathuni NS, Shah PS. Let's Get Physical: Flavivirus-Host Protein-Protein Interactions in Replication and Pathogenesis. Front Microbiol 2022; 13:847588. [PMID: 35308381 PMCID: PMC8928165 DOI: 10.3389/fmicb.2022.847588] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Flaviviruses comprise a genus of viruses that pose a significant burden on human health worldwide. Transmission by both mosquito and tick vectors, and broad host tropism contribute to the presence of flaviviruses globally. Like all viruses, they require utilization of host molecular machinery to facilitate their replication through physical interactions. Their RNA genomes are translated using host ribosomes, synthesizing viral proteins that cooperate with each other and host proteins to reshape the host cell into a factory for virus replication. Thus, dissecting the physical interactions between viral proteins and their host protein targets is essential in our comprehension of how flaviviruses replicate and how they alter host cell behavior. Beyond replication, even single interactions can contribute to immune evasion and pathogenesis, providing potential avenues for therapeutic intervention. Here, we review protein interactions between flavivirus and host proteins that contribute to virus replication, immune evasion, and disease.
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Affiliation(s)
- Adam T Fishburn
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States
| | - Oanh H Pham
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States
| | - Matthew W Kenaston
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States
| | - Nitin S Beesabathuni
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States.,Department of Chemical Engineering, University of California, Davis, Davis, CA, United States
| | - Priya S Shah
- Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States.,Department of Chemical Engineering, University of California, Davis, Davis, CA, United States
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15
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Talotta R, Bahrami S, Laska MJ. Sequence complementarity between human noncoding RNAs and SARS-CoV-2 genes: What are the implications for human health? Biochim Biophys Acta Mol Basis Dis 2022; 1868:166291. [PMID: 34662705 PMCID: PMC8518135 DOI: 10.1016/j.bbadis.2021.166291] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/17/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022]
Abstract
Objectives To investigate in silico the presence of nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human non-coding (nc)RNA genes. Methods The FASTA sequence (NC_045512.2) of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes was retrieved from NCBI.nlm.nih.gov/gene and the Ensembl.org library interrogated for any base-pair match with human ncRNA genes. SARS-CoV-2 gene-matched human ncRNAs were screened for functional activity using bioinformatic analysis. Finally, associations between identified ncRNAs and human diseases were searched in GWAS databases. Results A total of 252 matches were found between the nucleotide sequence of SARS-CoV-2 genes and human ncRNAs. With the exception of two small nuclear RNAs, all of them were long non-coding (lnc)RNAs expressed mainly in testis and central nervous system under physiological conditions. The percentage of alignment ranged from 91.30% to 100% with a mean nucleotide alignment length of 17.5 ± 2.4. Thirty-three (13.09%) of them contained predicted R-loop forming sequences, but none of these intersected the complementary sequences of SARS-CoV-2. However, in 31 cases matches fell on ncRNA regulatory sites, whose adjacent coding genes are mostly involved in cancer, immunological and neurological pathways. Similarly, several polymorphic variants of detected non-coding genes have been associated with neuropsychiatric and proliferative disorders. Conclusion This pivotal in silico study shows that SARS-CoV-2 genes have Watson-Crick nucleotide complementarity to human ncRNA sequences, potentially disrupting ncRNA epigenetic control of target genes. It remains to be elucidated whether this could result in the development of human disease in the long term.
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Affiliation(s)
- Rossella Talotta
- Department of Clinical and Experimental Medicine, Rheumatology Unit, AOU "Gaetano Martino", University of Messina, Messina, Italy.
| | - Shervin Bahrami
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
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16
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Li J, Boix E. Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses. Virulence 2021; 12:444-469. [PMID: 33660566 PMCID: PMC7939569 DOI: 10.1080/21505594.2021.1871823] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time. Here, we try to summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses. Overall, host RNases can fight viruses by a combined multifaceted strategy, including the enzymatic target of the viral genome, recognition of virus unique patterns, immune modulation, control of stress granule formation, and induction of autophagy/apoptosis pathways. The review also includes a detailed description of representative enveloped ssRNA viruses and their strategies to interact with the host and evade immune recognition. For comparative purposes, we also provide an exhaustive revision of the currently approved or experimental antiviral drugs. Finally, we sum up the current perspectives of drug development to achieve successful eradication of viral infections.
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Affiliation(s)
- Jiarui Li
- Dpt. Of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma De Barcelona, Spain
| | - Ester Boix
- Dpt. Of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma De Barcelona, Spain
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17
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In Silico Identification and Clinical Validation of a Novel Long Non-Coding RNA/mRNA/miRNA Molecular Network for Potential Biomarkers for Discriminating SARS CoV-2 Infection Severity. Cells 2021; 10:cells10113098. [PMID: 34831321 PMCID: PMC8625524 DOI: 10.3390/cells10113098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: The coronavirus (COVID-19) pandemic is still a major global health problem, despite the development of several vaccines and diagnostic assays. Moreover, the broad symptoms, from none to severe pneumonia, and the various responses to vaccines and the assays, make infection control challenging. Therefore, there is an urgent need to develop non-invasive biomarkers to quickly determine the infection severity. Circulating RNAs have been proven to be potential biomarkers for a variety of diseases, including infectious ones. This study aimed to develop a genetic network related to cytokines, with clinical validation for early infection severity prediction. (2) Methods: Extensive analyses of in silico data have established a novel IL11RA molecular network (IL11RNA mRNA, LncRNAs RP11-773H22.4 and hsa-miR-4257). We used different databases to confirm its validity. The differential expression within the retrieved network was clinically validated using quantitative RT-PCR, along with routine assessment diagnostic markers (CRP, LDH, D-dimmer, procalcitonin, Ferritin), in100 infected subjects (mild and severe cases) and 100 healthy volunteers. (3) Results: IL11RNA mRNA and LncRNA RP11-773H22.4, and the IL11RA protein, were significantly upregulated, and there was concomitant downregulation of hsa-miR-4257, in infected patients, compared to the healthy controls, in concordance with the infection severity. (4) Conclusion: The in-silico data and clinical validation led to the identification of a potential RNA/protein signature network for novel predictive biomarkers, which is in agreement with ferritin and procalcitonin for determination of COVID-19 severity.
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18
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Alveolar Regeneration in COVID-19 Patients: A Network Perspective. Int J Mol Sci 2021; 22:ijms222011279. [PMID: 34681944 PMCID: PMC8538208 DOI: 10.3390/ijms222011279] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.
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19
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Singh J, Raina A, Sangwan N, Chauhan A, Khanduja KL, Avti PK. Identification of homologous human miRNAs as antivirals towards COVID-19 genome. ADVANCES IN CELL AND GENE THERAPY 2021; 4:e114. [PMID: 34901760 PMCID: PMC8646656 DOI: 10.1002/acg2.114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/25/2021] [Accepted: 09/05/2021] [Indexed: 12/12/2022]
Abstract
The COVID-19 fatality rate is ~57% worldwide. The investigation of possible antiviral therapy using host microRNA (miRNA) to inhibit viral replication and transmission is the need of the hour. Computational techniques were used to predict the hairpin precursor miRNA (pre-miRNAs) of COVID-19 genome with high homology towards human (host) miRNA. Top 21 host miRNAs with >80% homology towards 18 viral pre miRNAs were identified. The Gibbs free energy (ΔG) between host miRNAs and viral pre-miRNAs hybridization resulted in the best 5 host miRNAs having the highest base-pair complementarity. miR-4476 had the strongest binding with viral pre-miRNA (ΔG = -21.8 kcal/mol) due to maximum base pairing in the seed sequence. Pre-miR-651 secondary structure was most stable due to the (1) least minimum free energy (ΔG = -24.4 kcal/mol), energy frequency, and noncanonical base pairing and (2) maximum number of stem base pairing and small loop size. Host miRNAs-viral mRNAs interaction can effectively inhibit viral transmission and replication. Furthermore, miRNAs gene network and gene-ontology studies indicate top 5 host miRNAs interaction with host genes involved in transmembrane-receptor signaling, cell migration, RNA splicing, nervous system formation, and tumor necrosis factor-mediated signaling in respiratory diseases. This study identifies host miRNA/virus pre-miRNAs strong interaction, structural stability, and their gene-network analysis provides strong evidence of host miRNAs as antiviral COVID-19 agents.
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Affiliation(s)
- Jitender Singh
- Department of BiophysicsPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Ashvinder Raina
- Postgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Namrata Sangwan
- Department of BiophysicsPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Arushi Chauhan
- Department of BiophysicsPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Krishan L. Khanduja
- Department of BiophysicsPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Pramod K. Avti
- Department of BiophysicsPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
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20
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Khatun M, Zhang J, Ray R, Ray RB. Hepatitis C Virus Evades Interferon Signaling by Suppressing Long Noncoding RNA Linc-Pint Involving C/EBP-β. J Virol 2021; 95:e0095221. [PMID: 34160260 PMCID: PMC8354323 DOI: 10.1128/jvi.00952-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 02/01/2023] Open
Abstract
Hepatitis C virus (HCV) regulates many cellular genes in modulating the host immune system for benefit of viral replication and long-term persistence in a host for chronic infection. Long noncoding RNAs (lncRNAs) play an important role in the regulation of many important cellular processes, including immune responses. We recently reported that HCV infection downregulates lncRNA Linc-Pint (long intergenic non-protein-coding RNA p53-induced transcript) expression, although the mechanism of repression and functional consequences are not well understood. In this study, we demonstrate that HCV infection of hepatocytes transcriptionally reduces Linc-Pint expression through CCAAT/enhancer binding protein β (C/EBP-β). Subsequently, we observed that the overexpression of Linc-Pint significantly upregulates interferon alpha (IFN-α) and IFN-β expression in HCV-replicating hepatocytes. Using unbiased proteomics, we identified that Linc-Pint associates with DDX24, which enables RIP1 to interact with IFN-regulatory factor 7 (IRF7) of the IFN signaling pathway. We furthermore observed that IFN-α14 promoter activity was enhanced in the presence of Linc-Pint. Together, these results demonstrated that Linc-Pint acts as a positive regulator of host innate immune responses, especially IFN signaling. HCV-mediated downregulation of Linc-Pint expression appears to be one of the mechanisms by which HCV may evade innate immunity for long-term persistence and chronicity. IMPORTANCE The mechanism by which lncRNA regulates the host immune response during HCV infection is poorly understood. We observed that Linc-Pint was transcriptionally downregulated by HCV. Using a chromatin immunoprecipitation (ChIP) assay, we showed inhibition of transcription factor C/EBP-β binding to the Linc-Pint promoter in the presence of HCV infection. We further identified that Linc-Pint associates with DDX24 for immunomodulatory function. The overexpression of Linc-Pint reduces DDX24 expression, which in turn results in the disruption of DDX24-RIP1 complex formation and the activation of IRF7. The induction of IFN-α14 promoter activity in the presence of Linc-Pint further confirms our observation. Together, our results suggest that Linc-Pint acts as a positive regulator of host innate immune responses. Downregulation of Linc-Pint expression by HCV helps in escaping the innate immune system for the development of chronicity.
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Affiliation(s)
- Mousumi Khatun
- Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA
| | - Jinsong Zhang
- Department of Pharmacology and Physiology, Saint Louis University, Saint Louis, Missouri, USA
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, Missouri, USA
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21
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Yang Q, Lin F, Wang Y, Zeng M, Luo M. Long Noncoding RNAs as Emerging Regulators of COVID-19. Front Immunol 2021; 12:700184. [PMID: 34408749 PMCID: PMC8366413 DOI: 10.3389/fimmu.2021.700184] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/15/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.
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Affiliation(s)
- Qinzhi Yang
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Fang Lin
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yanan Wang
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Min Zeng
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Mao Luo
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology of Department of Pharmacology, The School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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22
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Chen Y, Hu J, Liu S, Chen B, Xiao M, Li Y, Liao Y, Rai KR, Zhao Z, Ouyang J, Pan Q, Zhang L, Huang S, Chen JL. RDUR, a lncRNA, Promotes Innate Antiviral Responses and Provides Feedback Control of NF-κB Activation. Front Immunol 2021; 12:672165. [PMID: 34054851 PMCID: PMC8160526 DOI: 10.3389/fimmu.2021.672165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
Influenza A virus (IAV), a highly infectious respiratory pathogen, remains a major threat to global public health. Numerous long non-coding RNAs (lncRNAs) have been shown to be implicated in various cellular processes. Here, we identified a new lncRNA termed RIG-I-dependent IAV-upregulated noncoding RNA (RDUR), which was induced by infections with IAV and several other viruses. Both in vitro and in vivo studies revealed that robust expression of host RDUR induced by IAV was dependent on the RIG-I/NF-κB pathway. Overexpression of RDUR suppressed IAV replication and downregulation of RDUR promoted the virus replication. Deficiency of mouse RDUR increased virus production in lungs, body weight loss, acute organ damage and consequently reduced survival rates of mice, in response to IAV infection. RDUR impaired the viral replication by upregulating the expression of several vital antiviral molecules including interferons (IFNs) and interferon-stimulated genes (ISGs). Further study showed that RDUR interacted with ILF2 and ILF3 that were required for the efficient expression of some ISGs such as IFITM3 and MX1. On the other hand, we found that while NF-κB positively regulated the expression of RDUR, increased expression of RDUR, in turn, inactivated NF-κB through a negative feedback mechanism to suppress excessive inflammatory response to viral infection. Together, the results demonstrate that RDUR is an important lncRNA acting as a critical regulator of innate immunity against the viral infection.
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Affiliation(s)
- Yuhai Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Jiayue Hu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Shasha Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Biao Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China
| | - Meng Xiao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China
| | - Yingying Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China
| | - Yuan Liao
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Kul Raj Rai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China
| | - Zhonghui Zhao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China
| | - Jing Ouyang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Qidong Pan
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lianfeng Zhang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Beijing, China
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | - Ji-Long Chen
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
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23
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Choudhary C, Sharma S, Meghwanshi KK, Patel S, Mehta P, Shukla N, Do DN, Rajpurohit S, Suravajhala P, Shukla JN. Long Non-Coding RNAs in Insects. Animals (Basel) 2021; 11:1118. [PMID: 33919662 PMCID: PMC8069800 DOI: 10.3390/ani11041118] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 12/27/2022] Open
Abstract
Only a small subset of all the transcribed RNAs are used as a template for protein translation, whereas RNA molecules that are not translated play a very important role as regulatory non-coding RNAs (ncRNAs). Besides traditionally known RNAs (ribosomal and transfer RNAs), ncRNAs also include small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs). The lncRNAs, which were initially thought to be junk, have gained a great deal attention because of their regulatory roles in diverse biological processes in animals and plants. Insects are the most abundant and diverse group of animals on this planet. Recent studies have demonstrated the role of lncRNAs in almost all aspects of insect development, reproduction, and genetic plasticity. In this review, we describe the function and molecular mechanisms of the mode of action of different insect lncRNAs discovered up to date.
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Affiliation(s)
- Chhavi Choudhary
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindari, Ajmer 305801, India; (C.C.); (K.K.M.)
| | - Shivasmi Sharma
- Department of Biotechnology, Amity University Jaipur, Jaipur 303002, India; (S.S.); (S.P.)
| | - Keshav Kumar Meghwanshi
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindari, Ajmer 305801, India; (C.C.); (K.K.M.)
| | - Smit Patel
- Department of Biotechnology, Amity University Jaipur, Jaipur 303002, India; (S.S.); (S.P.)
| | - Prachi Mehta
- Division of Biological & Life Sciences, School of Arts and Sciences, Ahmedabad University, Gujarat 380009, India; (P.M.); (S.R.)
| | - Nidhi Shukla
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur 302001, India;
| | - Duy Ngoc Do
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam;
| | - Subhash Rajpurohit
- Division of Biological & Life Sciences, School of Arts and Sciences, Ahmedabad University, Gujarat 380009, India; (P.M.); (S.R.)
| | - Prashanth Suravajhala
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Jaipur 302001, India;
- Bioclues.org, Vivekananda Nagar, Kukatpally, Hyderabad, Telangana 500072, India
| | - Jayendra Nath Shukla
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindari, Ajmer 305801, India; (C.C.); (K.K.M.)
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24
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Lu L, Wei R, Prats-Ejarque G, Goetz M, Wang G, Torrent M, Boix E. Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model. Cell Mol Life Sci 2021; 78:2963-2985. [PMID: 33226440 PMCID: PMC8004517 DOI: 10.1007/s00018-020-03695-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 09/21/2020] [Accepted: 10/31/2020] [Indexed: 02/06/2023]
Abstract
The human RNase3 is a member of the RNaseA superfamily involved in host immunity. RNase3 is expressed by leukocytes and shows broad-spectrum antimicrobial activity. Together with a direct antimicrobial action, RNase3 exhibits immunomodulatory properties. Here, we have analysed the transcriptome of macrophages exposed to the wild-type protein and a catalytic-defective mutant (RNase3-H15A). The analysis of differently expressed genes (DEGs) in treated THP1-derived macrophages highlighted a common pro-inflammatory "core-response" independent of the protein ribonucleolytic activity. Network analysis identified the epidermal growth factor receptor (EGFR) as the main central regulatory protein. Expression of selected DEGs and MAPK phosphorylation were inhibited by an anti-EGFR antibody. Structural analysis suggested that RNase3 activates the EGFR pathway by direct interaction with the receptor. Besides, we identified a subset of DEGs related to the protein ribonucleolytic activity, characteristic of virus infection response. Transcriptome analysis revealed an early pro-inflammatory response, not associated to the protein catalytic activity, followed by a late activation in a ribonucleolytic-dependent manner. Next, we demonstrated that overexpression of macrophage endogenous RNase3 protects the cells against infection by Mycobacterium aurum and the human respiratory syncytial virus. Comparison of cell infection profiles in the presence of Erlotinib, an EGFR inhibitor, revealed that the receptor activation is required for the antibacterial but not for the antiviral protein action. Moreover, the DEGs related and unrelated to the protein catalytic activity are associated to the immune response to bacterial and viral infection, respectively. We conclude that RNase3 modulates the macrophage defence against infection in both catalytic-dependent and independent manners.
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Affiliation(s)
- Lu Lu
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Vallès, Spain
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - RanLei Wei
- Center of Precision Medicine and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Guillem Prats-Ejarque
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Vallès, Spain
| | - Maria Goetz
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Vallès, Spain
| | - Gang Wang
- Center of Precision Medicine and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Marc Torrent
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Vallès, Spain
| | - Ester Boix
- Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autonoma de Barcelona, Cerdanyola del Vallès, Spain.
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25
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Lange S, Arisan ED, Grant GH, Uysal-Onganer P. MicroRNAs for Virus Pathogenicity and Host Responses, Identified in SARS-CoV-2 Genomes, May Play Roles in Viral-Host Co-Evolution in Putative Zoonotic Host Species. Viruses 2021; 13:117. [PMID: 33467206 PMCID: PMC7830670 DOI: 10.3390/v13010117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/07/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022] Open
Abstract
Our recent study identified seven key microRNAs (miR-8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) similar between SARS-CoV-2 and the human genome, pointing at miR-related mechanisms in viral entry and the regulatory effects on host immunity. To identify the putative roles of these miRs in zoonosis, we assessed their conservation, compared with humans, in some key wild and domestic animal carriers of zoonotic viruses, including bat, pangolin, pig, cow, rat, and chicken. Out of the seven miRs under study, miR-3611 was the most strongly conserved across all species; miR-5197 was the most conserved in pangolin, pig, cow, bat, and rat; miR-1307 was most strongly conserved in pangolin, pig, cow, bat, and human; miR-3691-3p in pangolin, cow, and human; miR-3934-3p in pig and cow, followed by pangolin and bat; miR-1468 was most conserved in pangolin, pig, and bat; while miR-8066 was most conserved in pangolin and pig. In humans, miR-3611 and miR-1307 were most conserved, while miR-8066, miR-5197, miR-3334-3p and miR-1468 were least conserved, compared with pangolin, pig, cow, and bat. Furthermore, we identified that changes in the miR-5197 nucleotides between pangolin and human can generate three new miRs, with differing tissue distribution in the brain, lung, intestines, lymph nodes, and muscle, and with different downstream regulatory effects on KEGG pathways. This may be of considerable importance as miR-5197 is localized in the spike protein transcript area of the SARS-CoV-2 genome. Our findings may indicate roles for these miRs in viral-host co-evolution in zoonotic hosts, particularly highlighting pangolin, bat, cow, and pig as putative zoonotic carriers, while highlighting the miRs' roles in KEGG pathways linked to viral pathogenicity and host responses in humans. This in silico study paves the way for investigations into the roles of miRs in zoonotic disease.
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Affiliation(s)
- Sigrun Lange
- Tissue Architecture and Regeneration Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
| | - Elif Damla Arisan
- Institute of Biotechnology, Gebze Technical University, Gebze, 41400 Kocaeli, Turkey;
| | - Guy H. Grant
- School of Life Sciences, University of Bedfordshire, Park Square, Luton LU1 3JU, UK;
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
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26
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Carino EJ, Scheets K, Miller WA. The RNA of Maize Chlorotic Mottle Virus, an Obligatory Component of Maize Lethal Necrosis Disease, Is Translated via a Variant Panicum Mosaic Virus-Like Cap-Independent Translation Element. J Virol 2020; 94:e01005-20. [PMID: 32847851 PMCID: PMC7592216 DOI: 10.1128/jvi.01005-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/30/2020] [Indexed: 11/29/2022] Open
Abstract
Maize chlorotic mottle virus (MCMV) combines with a potyvirus in maize lethal necrosis disease (MLND), a serious emerging disease worldwide. To inform resistance strategies, we characterized the translation initiation mechanism of MCMV. We report that MCMV RNA contains a cap-independent translation element (CITE) in its 3' untranslated region (UTR). The MCMV 3' CITE (MTE) was mapped to nucleotides 4164 to 4333 in the genomic RNA. 2'-Hydroxyl acylation analyzed by primer extension (SHAPE) probing revealed that the MTE is a distinct variant of the panicum mosaic virus-like 3' CITE (PTE). Like the PTE, electrophoretic mobility shift assays (EMSAs) indicated that eukaryotic translation initiation factor 4E (eIF4E) binds the MTE despite the absence of an m7GpppN cap structure, which is normally required for eIF4E to bind RNA. Using a luciferase reporter system, mutagenesis to disrupt and restore base pairing revealed that the MTE interacts with the 5' UTRs of both genomic RNA and subgenomic RNA1 via long-distance kissing stem-loop interaction to facilitate translation. The MTE stimulates a relatively low level of translation and has a weak, if any, pseudoknot, which is present in the most active PTEs, mainly because the MTE lacks the pyrimidine-rich tract that base pairs to a G-rich bulge to form the pseudoknot. However, most mutations designed to form a pseudoknot decreased translation activity. Mutations in the viral genome that reduced or restored translation prevented and restored virus replication, respectively, in maize protoplasts and in plants. In summary, the MTE differs from the canonical PTE but falls into a structurally related class of 3' CITEs.IMPORTANCE In the past decade, maize lethal necrosis disease has caused massive crop losses in East Africa. It has also emerged in China and parts of South America. Maize chlorotic mottle virus (MCMV) infection is required for this disease. While some tolerant maize lines have been identified, there are no known resistance genes that confer immunity to MCMV. In order to improve resistance strategies against MCMV, we focused on how the MCMV genome is translated, the first step of gene expression by all positive-strand RNA viruses. We identified a structure (cap-independent translation element) in the 3' untranslated region of the viral RNA genome that allows the virus to usurp a host translation initiation factor, eIF4E, in a way that differs from host mRNA interactions with the translational machinery. This difference indicates eIF4E may be a soft target for engineering of-or breeding for-resistance to MCMV.
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Affiliation(s)
- Elizabeth J Carino
- Department of Plant Pathology and Microbiology, Iowa State University, Ames, Iowa, USA
- Interdepartmental Genetics and Genomics Program, Iowa State University, Ames, Iowa, USA
| | - Kay Scheets
- Department of Plant Biology, Ecology and Evolution, Oklahoma State University, Stillwater, Oklahoma, USA
| | - W Allen Miller
- Department of Plant Pathology and Microbiology, Iowa State University, Ames, Iowa, USA
- Interdepartmental Genetics and Genomics Program, Iowa State University, Ames, Iowa, USA
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27
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Gallo A, Bulati M, Miceli V, Amodio N, Conaldi PG. Non-Coding RNAs: Strategy for Viruses' Offensive. Noncoding RNA 2020; 6:38. [PMID: 32927786 PMCID: PMC7549346 DOI: 10.3390/ncrna6030038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
The awareness of viruses as a constant threat for human public health is a matter of fact and in this resides the need of understanding the mechanisms they use to trick the host. Viral non-coding RNAs are gaining much value and interest for the potential impact played in host gene regulation, acting as fine tuners of host cellular defense mechanisms. The implicit importance of v-ncRNAs resides first in the limited genomes size of viruses carrying only strictly necessary genomic sequences. The other crucial and appealing characteristic of v-ncRNAs is the non-immunogenicity, making them the perfect expedient to be used in the never-ending virus-host war. In this review, we wish to examine how DNA and RNA viruses have evolved a common strategy and which the crucial host pathways are targeted through v-ncRNAs in order to grant and facilitate their life cycle.
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Affiliation(s)
- Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy;
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Via E.Tricomi 5, 90127 Palermo, Italy; (M.B.); (V.M.); (P.G.C.)
- UPMC Italy (University of Pittsburgh Medical Center Italy), Discesa dei Giudici 4, 90133 Palermo, Italy
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28
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Turjya RR, Khan MAAK, Mir Md. Khademul Islam AB. Perversely expressed long noncoding RNAs can alter host response and viral proliferation in SARS-CoV-2 infection. Future Virol 2020; 15:577-593. [PMID: 33224264 PMCID: PMC7664154 DOI: 10.2217/fvl-2020-0188] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Regulatory roles of long noncoding RNAs (lncRNAs) during viral infection has become more evident in last decade, but are yet to be explored for SARS-CoV-2. MATERIALS & METHODS We analyzed RNA-seq dataset of SARS-CoV-2 infected lung epithelial cells to identify differentially expressed genes. RESULTS Our analyses uncover 21 differentially expressed lncRNAs broadly involved in cell survival and regulation of gene expression. These lncRNAs can directly interact with six differentially expressed protein-coding genes, and ten host genes that interact with SARS-CoV-2 proteins. Also, they can block the suppressive effect of nine microRNAs induced in viral infections. CONCLUSION Our investigation determines that deregulated lncRNAs in SARS-CoV-2 infection are involved in viral proliferation, cellular survival, and immune response, ultimately determining disease outcome.
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Affiliation(s)
- Rafeed Rahman Turjya
- Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh
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29
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Kokkonos KG, Fossat N, Nielsen L, Holm C, Hepkema WM, Bukh J, Scheel TKH. Evolutionary selection of pestivirus variants with altered or no microRNA dependency. Nucleic Acids Res 2020; 48:5555-5571. [PMID: 32374844 PMCID: PMC7261151 DOI: 10.1093/nar/gkaa300] [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: 03/26/2020] [Accepted: 04/19/2020] [Indexed: 12/15/2022] Open
Abstract
Host microRNA (miRNA) dependency is a hallmark of the human pathogen hepatitis C virus (HCV) and was also described for the related pestiviruses, which are important livestock pathogens. The liver-specific miR-122 binds within the HCV 5′ untranslated region (UTR), whereas the broadly expressed let-7 and miR-17 families bind two sites (S1 and S2, respectively) in the pestiviral 3′ UTR. Here, we dissected the mechanism of miRNA dependency of the pestivirus bovine viral diarrhea virus (BVDV). Argonaute 2 (AGO2) and miR-17 binding were essential for viral replication, whereas let-7 binding was mainly required for full translational efficiency. Furthermore, using seed site randomized genomes and evolutionary selection experiments, we found that tropism could be redirected to different miRNAs. AGO cross-linking and immunoprecipitation (CLIP) experiments and miRNA antagonism demonstrated that these alternative variants bound and depended on the corresponding miRNAs. Interestingly, we also identified miRNA-independent variants that were obtained through acquisition of compensatory mutations near the genomic 3′ terminus. Rescue experiments demonstrated that miRNA binding and 3′ mutagenesis contribute to replication through mutually exclusive mechanisms. Altogether, our findings suggest that pestiviruses, although capable of miRNA-independent replication, took advantage of miRNAs as essential host factors, suggesting a favorable path during evolutionary adaptation.
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Affiliation(s)
- Konstantinos G Kokkonos
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Nicolas Fossat
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Louise Nielsen
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Christina Holm
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Wytske M Hepkema
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Troels K H Scheel
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, Hvidovre 2650, Denmark.,Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.,Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
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30
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Li H, Tang W, Jin Y, Dong W, Yan Y, Zhou J. Differential CircRNA Expression Profiles in PK-15 Cells Infected with Pseudorabies Virus Type II. Virol Sin 2020; 36:75-84. [PMID: 32617900 DOI: 10.1007/s12250-020-00255-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 05/26/2020] [Indexed: 12/21/2022] Open
Abstract
Circular RNAs (circRNAs) belong to a class of non-coding RNAs with diverse biological functions. However, little is known about their roles in case of pseudorabies virus (PrV) infection. Here, we analyzed the expression profile of host circRNAs from a virulent PrV type II strain DX (PrV-DX) infected and an attenuated gE/TK deficient (gE-TK-PrV) strain of PrV infected PK-15 cells. CircRNAs were identified by find_circ and analyzed with DESeq 2. Compared with the mock cells, 449 differentially expressed (DE) circRNAs (233 down-regulated and 216 up-regulated) from PrV-DX infected and 578 DE circRNAs (331 down-regulated and 247 up-regulated) from gE-TK- PrV infected PK-15 cells were identified. In addition, 459 DE circRNAs (164 down-regulated and 295 up-regulated) between the PrV-DX and gE-TK-PrV infected cells were identified. The expression patterns of 13 circRNAs were validated by reverse transcription quantitative real-time PCR (RT-qPCR) and results were similar as of RNA-seq. The putative target miRNA binding sites of DE circRNAs were predicted by using miRanda and psRobot. The circRNA-miRNA-mRNA network was constructed and certain miRNAs that have possible roles in antiviral immune response, such as miR-210 and miR-340, were predicted. GO and KEGG pathway analysis demonstrated that DE circRNAs were enriched in the processes such as cellular metabolism, protein binding, RNA degradation and regulation of actin cytoskeleton. Collectively, these findings might provide the useful information for a better understanding of mechanisms underlying the interaction between PrV-II and host cells.
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Affiliation(s)
- Haimin Li
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wen Tang
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yulan Jin
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Weiren Dong
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yan Yan
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jiyong Zhou
- MOA Key Laboratory of Animal Virology, Center of Veterinary Sciences, Zhejiang University, Hangzhou, 310058, China.
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31
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Zhang J, Li X, Hu J, Cao P, Yan Q, Zhang S, Dang W, Lu J. Long noncoding RNAs involvement in Epstein-Barr virus infection and tumorigenesis. Virol J 2020; 17:51. [PMID: 32272952 PMCID: PMC7146903 DOI: 10.1186/s12985-020-01308-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/27/2020] [Indexed: 02/08/2023] Open
Abstract
The Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus related to various types of cancers, including epithelial nasopharyngeal carcinoma, gastric carcinoma, and lymphoma. Long noncoding RNAs (lncRNAs) are expressed extensively in mammalian cells and play crucial roles in regulating various cellular processes and multiple cancers. Cellular lncRNAs can be differentially expressed induced by EBV infection. The dysregulated lncRNAs probably modulate the host immune response and other biological functions. At present, lncRNAs have been found to be significantly increased or decreased in EBV-infected cells, exosomes and EBV-associated cancers, suggesting their potential function and clinical application as biomarkers. In addition, EBV-encoded lncRNAs, BART and BHLF1 lncRNAs, may play roles in the viral oncogenesis. Analysis of the specific lncRNAs involved in interactions with the EBV machinery will provide information on their potential mechanism of action during multiple steps of EBV tumorigenesis. Here, we review the current knowledge regarding EBV-related lncRNAs and their possible roles in the pathogenesis of EBV-associated cancers.
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Affiliation(s)
- Jing Zhang
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Xiaohan Li
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Jingjin Hu
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Pengfei Cao
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China
| | - Qijia Yan
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China
| | - Siwei Zhang
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Wei Dang
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, China
| | - Jianhong Lu
- NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, China. .,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, China.
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32
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Bakre AA, Maleki A, Tripp RA. MicroRNA and Nonsense Transcripts as Putative Viral Evasion Mechanisms. Front Cell Infect Microbiol 2019; 9:152. [PMID: 31139579 PMCID: PMC6519394 DOI: 10.3389/fcimb.2019.00152] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/23/2019] [Indexed: 12/25/2022] Open
Abstract
Viral proteins encode numerous antiviral activities to modify the host immunity. In this article, we hypothesize that viral genomes and gene transcripts interfere with host gene expression using passive mechanisms to deregulate host microRNA (miRNA) activity. We postulate that various RNA viruses mimic or block binding between a host miRNA and its target transcript, a phenomenon mediated by the miRNA seed site at the 5′ end of miRNA. Virus-encoded miRNA seed sponges (vSSs) can potentially bind to host miRNA seed sites and prevent interaction with their native targets thereby relieving native miRNA suppression. In contrast, virus-encoded miRNA seed mimics (vSMs) may mediate considerable downregulation of host miRNA activity. We analyzed genomes from diverse RNA viruses for vSS and vSM signatures and found an abundance of these motifs indicating that this may be a mechanism of deceiving host immunity. Employing respiratory syncytial virus and measles virus as models, we reveal that regions surrounding vSS or vSM motifs have features characteristics of pre-miRNA templates and show that RSV viral transcripts are processed into small RNAs that may behave as vSS or vSM effectors. These data suggest that complex molecular interactions likely occur at the host-virus interface. Identifying the mechanisms in the network of interactions between the host and viral transcripts can help uncover ways to improve vaccine efficacy, therapeutics, and potentially mitigate the adverse events that may be associated with some vaccines.
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Affiliation(s)
- Abhijeet A Bakre
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - Ali Maleki
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ralph A Tripp
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
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