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Non-coding RNAs in Pathogen-Host Interaction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 26879

Special Issue Editor

Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
Interests: non-coding RNA; nc886; cancer; innate immunity; RNA-protein interaction; protein kinase R (PKR); dicer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-coding RNAs (ncRNAs), particularly their fascinating gene-regulatory function, have burst onto the research scene for the last two decades. This trend began by the discovery of microRNAs (miRNAs) and upsurged by long ncRNAs (lncRNAs). The boom of ncRNA study was catalysed by revolutionary advancement in technology. The next generation sequencing technique has vastly widened the repertoire of ncRNAs. We foresee that more ncRNAs will be excavated, given that the majority of the human genome is transcribed to RNAs but only 1~2% of them are translated into proteins. Now it is clear that expression of numerous ncRNAs is tissue- and cell type- specific and is dysregulated in diseases, suggesting that those ncRNAs affect normal developmental programs and pathological processes.

Currently, the tragic coronavirus pandemic is influencing our daily life and so research endeavours are urgently needed. Accordingly, we will focus on pathogen-host interaction in this special issue. In regard to an ncRNA’s biological role and molecular function, some ncRNA classes have been extensively studied. Best examples are miRNAs in post-transcriptional regulation and nuclear lncRNAs in epigenetic control. However, a significant fraction of ncRNAs, especially recently discovered ones, have not been examined in sufficient depth. Thus, we will give priority to those underrated ncRNAs although well-studied ncRNA classes will be also welcomed.

Collectively, in this special issue, we will recruit manuscripts on ncRNAs in pathogen-host interaction. This topic includes (but is not limited to) host- or virally-encoded ncRNAs that play a role in host immunity, viral replication, and associated host disorders such as infectious diseases and cancer. We look forward to novel and fascinating research outcomes.

Dr. Yong Sun Lee
Guest Editor

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Keywords

  • non-coding RNA
  • pathogen
  • immune response
  • infectious diseases

Published Papers (10 papers)

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Editorial

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2 pages, 163 KiB  
Editorial
Editorial of Special Issue “Non-Coding RNAs in Pathogen-Host Interaction”
by Yong Sun Lee
Int. J. Mol. Sci. 2021, 22(21), 11346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111346 - 21 Oct 2021
Viewed by 1301
Abstract
Clinical outcomes after pathologic infection are variable in infected individuals, ranging from no symptoms, moderate symptoms, hospitalization, and even death [...] Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)

Research

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13 pages, 4919 KiB  
Article
Monocyte-Derived miRNA-1914-5p Attenuates IL-1β–Induced Monocyte Adhesion and Transmigration
by Kohki Toriuchi, Toshie Kihara, Hiromasa Aoki, Hiroki Kakita, Satoru Takeshita, Hiroko Ueda, Yasumichi Inoue, Hidetoshi Hayashi, Yohei Shimono, Yasumasa Yamada and Mineyoshi Aoyama
Int. J. Mol. Sci. 2023, 24(3), 2829; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032829 - 01 Feb 2023
Cited by 3 | Viewed by 1381
Abstract
Atherosclerosis can lead to cardiovascular and cerebrovascular diseases. Atherosclerotic plaque formation is promoted by the accumulation of inflammatory cells. Therefore, modulating monocyte recruitment represents a potential therapeutic strategy. In an inflammatory state, the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) [...] Read more.
Atherosclerosis can lead to cardiovascular and cerebrovascular diseases. Atherosclerotic plaque formation is promoted by the accumulation of inflammatory cells. Therefore, modulating monocyte recruitment represents a potential therapeutic strategy. In an inflammatory state, the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) is upregulated in endothelial cells. We previously reported that miR-1914-5p in endothelial cells suppresses interleukin (IL)-1β–induced ICAM-1 expression and monocyte adhesion to endothelial cells. However, whether monocyte miR-1914-5p affects monocyte recruitment is unclear. In this study, IL-1β decreased miR-1914-5p expression in a human monocyte cell line. Moreover, miR-1914-5p inhibition enhanced adhesion to endothelial cells with the upregulation of macrophage-1 antigen (Mac-1), a counter-ligand to ICAM-1. Transmigration through the endothelial layer was also promoted with the upregulation of monocyte chemotactic protein-1 (MCP-1). Furthermore, a miR-1914-5p mimic suppressed IL-1β–induced monocyte adhesion and transmigration in monocytes with Mac-1 and MCP-1 downregulation. Further investigation of miR-1914-5p in monocytes could lead to the development of novel diagnostic markers and therapeutic strategies for atherosclerosis. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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15 pages, 2241 KiB  
Article
The Interaction of Human and Epstein–Barr Virus miRNAs with Multiple Sclerosis Risk Loci
by Ali Afrasiabi, Nicole L. Fewings, Stephen D. Schibeci, Jeremy T. Keane, David R. Booth, Grant P. Parnell and Sanjay Swaminathan
Int. J. Mol. Sci. 2021, 22(6), 2927; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062927 - 13 Mar 2021
Cited by 19 | Viewed by 3082
Abstract
Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to [...] Read more.
Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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13 pages, 1746 KiB  
Article
Nc886, a Novel Suppressor of the Type I Interferon Response Upon Pathogen Intrusion
by Yeon-Su Lee, Xiaoyong Bao, Hwi-Ho Lee, Jiyoung Joan Jang, Enkhjin Saruuldalai, Gaeul Park, Wonkyun Ronny Im, Jong-Lyul Park, Seon-Young Kim, Sooyong Shin, Sung Ho Jeon, Sangmin Kang, Hyun-Sung Lee, Ju-Seog Lee, Ke Zhang, Eun Jung Park, In-Hoo Kim and Yong Sun Lee
Int. J. Mol. Sci. 2021, 22(4), 2003; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042003 - 18 Feb 2021
Cited by 9 | Viewed by 2622
Abstract
Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because [...] Read more.
Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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24 pages, 7508 KiB  
Article
PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway
by Abdelrahman M. Elsayed, Emine Bayraktar, Paola Amero, Salama A. Salama, Abdelaziz H. Abdelaziz, Raed S. Ismail, Xinna Zhang, Cristina Ivan, Anil K. Sood, Gabriel Lopez-Berestein and Cristian Rodriguez-Aguayo
Int. J. Mol. Sci. 2021, 22(4), 1882; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041882 - 13 Feb 2021
Cited by 12 | Viewed by 2667
Abstract
Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. [...] Read more.
Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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13 pages, 1604 KiB  
Article
Human DDX3X Unwinds Japanese Encephalitis and Zika Viral 5′ Terminal Regions
by Corey Nelson, Tyler Mrozowich, Darren L. Gemmill, Sean M. Park and Trushar R. Patel
Int. J. Mol. Sci. 2021, 22(1), 413; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010413 - 02 Jan 2021
Cited by 13 | Viewed by 3479
Abstract
Flavivirus genus includes many deadly viruses such as the Japanese encephalitis virus (JEV) and Zika virus (ZIKV). The 5′ terminal regions (TR) of flaviviruses interact with human proteins and such interactions are critical for viral replication. One of the human proteins identified to [...] Read more.
Flavivirus genus includes many deadly viruses such as the Japanese encephalitis virus (JEV) and Zika virus (ZIKV). The 5′ terminal regions (TR) of flaviviruses interact with human proteins and such interactions are critical for viral replication. One of the human proteins identified to interact with the 5′ TR of JEV is the DEAD-box helicase, DDX3X. In this study, we in vitro transcribed the 5′ TR of JEV and demonstrated its direct interaction with recombinant DDX3X (Kd of 1.66 ± 0.21 µM) using microscale thermophoresis (MST). Due to the proposed structural similarities of 5′ and 3′ TRs of flaviviruses, we investigated if the ZIKV 5′ TR could also interact with human DDX3X. Our MST studies suggested that DDX3X recognizes ZIKV 5′ TR with a Kd of 7.05 ± 0.75 µM. Next, we performed helicase assays that suggested that the binding of DDX3X leads to the unwinding of JEV and ZIKV 5′ TRs. Overall, our data indicate, for the first time, that DDX3X can directly bind and unwind in vitro transcribed flaviviral TRs. In summary, our work indicates that DDX3X could be further explored as a therapeutic target to inhibit Flaviviral replication Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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17 pages, 2691 KiB  
Article
Human DDX17 Unwinds Rift Valley Fever Virus Non-Coding RNAs
by Corey R. Nelson, Tyler Mrozowich, Sean M. Park, Simmone D’souza, Amy Henrickson, Justin R. J. Vigar, Hans-Joachim Wieden, Raymond J. Owens, Borries Demeler and Trushar R. Patel
Int. J. Mol. Sci. 2021, 22(1), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010054 - 23 Dec 2020
Cited by 17 | Viewed by 3733
Abstract
Rift Valley fever virus (RVFV) is a mosquito-transmitted virus from the Bunyaviridae family that causes high rates of mortality and morbidity in humans and ruminant animals. Previous studies indicated that DEAD-box helicase 17 (DDX17) restricts RVFV replication by recognizing two primary non-coding RNAs [...] Read more.
Rift Valley fever virus (RVFV) is a mosquito-transmitted virus from the Bunyaviridae family that causes high rates of mortality and morbidity in humans and ruminant animals. Previous studies indicated that DEAD-box helicase 17 (DDX17) restricts RVFV replication by recognizing two primary non-coding RNAs in the S-segment of the genome: the intergenic region (IGR) and 5′ non-coding region (NCR). However, we lack molecular insights into the direct binding of DDX17 with RVFV non-coding RNAs and information on the unwinding of both non-coding RNAs by DDX17. Therefore, we performed an extensive biophysical analysis of the DDX17 helicase domain (DDX17135–555) and RVFV non-coding RNAs, IGR and 5’ NCR. The homogeneity studies using analytical ultracentrifugation indicated that DDX17135–555, IGR, and 5’ NCR are pure. Next, we performed small-angle X-ray scattering (SAXS) experiments, which suggested that DDX17 and both RNAs are homogenous as well. SAXS analysis also demonstrated that DDX17 is globular to an extent, whereas the RNAs adopt an extended conformation in solution. Subsequently, microscale thermophoresis (MST) experiments were performed to investigate the direct binding of DDX17 to the non-coding RNAs. The MST experiments demonstrated that DDX17 binds with the IGR and 5’ NCR with a dissociation constant of 5.77 ± 0.15 µM and 9.85 ± 0.11 µM, respectively. As DDX17135–555 is an RNA helicase, we next determined if it could unwind IGR and NCR. We developed a helicase assay using MST and fluorescently-labeled oligos, which suggested DDX17135–555 can unwind both RNAs. Overall, our study provides direct evidence of DDX17135–555 interacting with and unwinding RVFV non-coding regions. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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11 pages, 1815 KiB  
Article
The Importance of AGO 1 and 4 in Post-Transcriptional Gene Regulatory Function of tRF5-GluCTC, an Respiratory Syncytial Virus-Induced tRNA-Derived RNA Fragment
by Eun-Jin Choi, Junping Ren, Ke Zhang, Wenzhe Wu, Yong Sun Lee, Inhan Lee and Xiaoyong Bao
Int. J. Mol. Sci. 2020, 21(22), 8766; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228766 - 20 Nov 2020
Cited by 17 | Viewed by 2203
Abstract
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, the elderly, and immune-compromised patients. It is also a significant contributor to upper respiratory tract infection in the pediatric population. However, its disease mechanisms are still largely [...] Read more.
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, the elderly, and immune-compromised patients. It is also a significant contributor to upper respiratory tract infection in the pediatric population. However, its disease mechanisms are still largely unknown. We have recently shown that a tRNA-derived RNA fragment (tRF) from the 5′-end of mature tRNA encoding GluCTC (tRF5-GluCTC), a recently discovered non-coding RNA, is functionally important for RSV replication and host gene regulation at the post-transcriptional level. However, how tRF5-GluCTC carries out the gene regulation is not fully known. In this study, we found that tRF5-GluCTC has impaired gene trans-silencing function in cells deficient of AGO1 or 4, while AGO2 and 3 seem not involved in tRF5-GluCTC-mediated gene regulation. By pulling down individual AGO protein, we discovered that tRF5-GluCTC is detectable only in the AGO4 complex, confirming the essential role of AGO4 in gene regulation and also suggesting that AGO1 contributes to the gene trans-silencing activity of tRF5-GluCTC in an atypical way. We also found that the P protein of RSV is associated with both AGO1 and 4 and AGO4 deficiency leads to reduced infectious viral particles. In summary, this study demonstrates the importance of AGO1 and 4 in mediating the gene trans-silencing function of tRF5-GluCTC. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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Review

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16 pages, 1150 KiB  
Review
MicroRNA Interference in Hepatic Host-Pathogen Interactions
by Asahiro Morishita, Kyoko Oura, Tomoko Tadokoro, Koji Fujita, Joji Tani and Tsutomu Masaki
Int. J. Mol. Sci. 2021, 22(7), 3554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073554 - 30 Mar 2021
Cited by 13 | Viewed by 2793
Abstract
The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. [...] Read more.
The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. Understanding the mechanistic details of interactions between hepatic host immune cells, including Kupffer cells and lymphocytes, and various hepatic pathogens, especially viruses, bacteria, and parasites, is necessary. MicroRNAs (miRNAs), over 2600 of which have been discovered, are small, endogenous, interfering, noncoding RNAs that are predicted to regulate more than 15,000 genes by degrading specific messenger RNAs. Several recent studies have demonstrated that some miRNAs are associated with the immune response to pathogens in the liver. However, the details of the underlying mechanisms of miRNA interference in hepatic host–pathogen interactions still remain elusive. In this review, we summarize the relationship between the immunological interactions of various pathogens and hepatic resident immune cells, as well as the role of miRNAs in the maintenance of liver immunity against pathogens. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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17 pages, 2292 KiB  
Review
Essential Role of Non-Coding RNAs in Enterovirus Infection: From Basic Mechanisms to Clinical Prospects
by Peiyu Zhu, Shuaiyin Chen, Weiguo Zhang, Guangcai Duan and Yuefei Jin
Int. J. Mol. Sci. 2021, 22(6), 2904; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062904 - 12 Mar 2021
Cited by 7 | Viewed by 2671
Abstract
Enteroviruses (EVs) are common RNA viruses that can cause various types of human diseases and conditions such as hand, foot, and mouth disease (HFMD), myocarditis, meningitis, sepsis, and respiratory disorders. Although EV infections in most patients are generally mild and self-limiting, a small [...] Read more.
Enteroviruses (EVs) are common RNA viruses that can cause various types of human diseases and conditions such as hand, foot, and mouth disease (HFMD), myocarditis, meningitis, sepsis, and respiratory disorders. Although EV infections in most patients are generally mild and self-limiting, a small number of young children can develop serious complications such as encephalitis, acute flaccid paralysis, myocarditis, and cardiorespiratory failure, resulting in fatalities. Established evidence has suggested that certain non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the occurrence and progression of many human diseases. Recently, the involvement of ncRNAs in the course of EV infection has been reported. Herein, the authors focus on recent advances in the understanding of ncRNAs in EV infection from basic viral pathogenesis to clinical prospects, providing a reference basis and new ideas for disease prevention and research directions. Full article
(This article belongs to the Special Issue Non-coding RNAs in Pathogen-Host Interaction)
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