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Special Issue "DNA or RNA-Mediated Innate Immune Response"

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 (15 June 2021) | Viewed by 11063

Special Issue Editors

Dr. Tomozumi Imamichi
E-Mail Website
Guest Editor
Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Interests: HIV; viral fitness; innat immunity; non-coding RNA; autophage; Interleukin-27; Interferon lambda-1; reactive oxygen specises
Dr. Hongyan Sui
E-Mail
Guest Editor
Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
Interests: all forms of RNA or DNA, including siRNA, miRNA, long non-coding RNA, DNA virus pathengen-induced Interferons and inflammatory cytokines, especially the mechanism of type III interferon inducing pathway

Special Issue Information

Dear Colleagues,

Innate immunity is the first line of defense and relies on germline-encoded pattern recognition receptors (PRRs) that primarily recognize conserved microbial molecules termed pathogen-associated molecular patterns (PAMPs). It has been known for over a decade that DNA or RNA, the most recognizable unit of life, is a potent trigger of induction interferons and proinflammatory cytokines in cells. Nucleic acids and their derivatives are one of the most important groups of PAMPs, particularly in the innate immune response against viruses. Research in the last decade has led to the identification and characterization of an increasing number of extracellular and intracellular PRRs. Two main classes of PRRs have been described in mammalian cells: membrane-bound receptors, such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and cytoplasmic sensors, including NOD-like receptors (NLRs), pyrin and HIN domain-containing (PYHIN) family members, RIG-I-like receptors (RLRs), and an increasing range of cytosolic nucleic acid sensors. However, how a new pathogen is recognized and how innate immune responses are initiated in different tissues or cells remain case-by-case questions. In turn, viruses have strategies to escape from the innate immure response by suppressing the signal pathway involved in the immune responses.

This Special Issue “DNA or RNA-Mediated Innate Immune Response” will cover a selection of original research articles, short communications, and current review articles in all areas of DNA or RNA-mediated innate immunity.

Dr. Tomozumi Imamichi
Dr. Hongyan Sui
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • innate immunity
  • interferons
  • inflammatory cytokines
  • pattern recognition receptors (PRRs)
  • pathogen-associated molecular patterns (PAMPs)

Published Papers (9 papers)

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Research

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Article
HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients
Int. J. Mol. Sci. 2021, 22(14), 7643; https://doi.org/10.3390/ijms22147643 - 16 Jul 2021
Cited by 2 | Viewed by 792
Abstract
NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by [...] Read more.
NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Article
Megalocytivirus Induces Complicated Fish Immune Response at Multiple RNA Levels Involving mRNA, miRNA, and circRNA
Int. J. Mol. Sci. 2021, 22(6), 3156; https://doi.org/10.3390/ijms22063156 - 19 Mar 2021
Cited by 2 | Viewed by 817
Abstract
Megalocytivirus is an important viral pathogen to many farmed fishes, including Japanese flounder (Paralichthys olivaceus). In this study, we examined megalocytivirus-induced RNA responses in the spleen of flounder by high-throughput sequencing and integrative analysis of various RNA-seq data. A total of [...] Read more.
Megalocytivirus is an important viral pathogen to many farmed fishes, including Japanese flounder (Paralichthys olivaceus). In this study, we examined megalocytivirus-induced RNA responses in the spleen of flounder by high-throughput sequencing and integrative analysis of various RNA-seq data. A total of 1327 microRNAs (miRNAs), including 368 novel miRNAs, were identified, among which, 171 (named DEmiRs) exhibited significantly differential expressions during viral infection in a time-dependent manner. For these DEmiRs, 805 differentially expressed target mRNAs (DETmRs) were predicted, whose expressions not only significantly changed after megalocytivirus infection but were also negatively correlated with their paired DEmiRs. Integrative analysis of immune-related DETmRs and their target DEmiRs identified 12 hub DEmiRs, which, together with their corresponding DETmRs, formed an interaction network containing 84 pairs of DEmiR and DETmR. In addition to DETmRs, 19 DEmiRs were also found to regulate six key immune genes (mRNAs) differentially expressed during megalocytivirus infection, and together they formed a network consisting of 21 interactive miRNA-messenger RNA (mRNA) pairs. Further analysis identified 9434 circular RNAs (circRNAs), 169 of which (named DEcircRs) showed time-specific and significantly altered expressions during megalocytivirus infection. Integrated analysis of the DETmR-DEmiR and DEcircR-DEmiR interactions led to the identification of a group of competing endogenous RNAs (ceRNAs) constituted by interacting triplets of circRNA, miRNA, and mRNA involved in antiviral immunity. Together these results indicate that complicated regulatory networks of different types of non-coding RNAs and coding RNAs are involved in megalocytivirus infection. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Article
MicroRNA Profiles in Monocyte-Derived Macrophages Generated by Interleukin-27 and Human Serum: Identification of a Novel HIV-Inhibiting and Autophagy-Inducing MicroRNA
Int. J. Mol. Sci. 2021, 22(3), 1290; https://doi.org/10.3390/ijms22031290 - 28 Jan 2021
Cited by 2 | Viewed by 782
Abstract
Interleukin-27 (IL-27) is a pleiotropic cytokine that influences the innate and adaptive immune systems. It inhibits viral infection and regulates the expression of microRNAs (miRNAs). We recently reported that macrophages differentiated from human primary monocytes in the presence of IL-27 and human AB [...] Read more.
Interleukin-27 (IL-27) is a pleiotropic cytokine that influences the innate and adaptive immune systems. It inhibits viral infection and regulates the expression of microRNAs (miRNAs). We recently reported that macrophages differentiated from human primary monocytes in the presence of IL-27 and human AB serum resisted human immunodeficiency virus (HIV) infection and showed significant autophagy induction. In the current study, the miRNA profiles in these cells were investigated, especially focusing on the identification of novel miRNAs regulated by IL-27-treatment. The miRNA sequencing analysis detected 38 novel miRNAs. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed that IL-27 differentially regulated the expression of 16 of the 38 miRNAs. Overexpression of the synthesized miRNA mimics by transfection revealed that miRAB40 had potent HIV-inhibiting and autophagy-inducing properties. B18R, an interferon (IFN)-neutralization protein, partially suppressed both activities, indicating that the two functions were induced via IFN-dependent and -independent pathways. Although the target mRNA(s) of miRAB40 involving in the induction of both functions was unable to identify in this study, the discovery of miRAB40, a potential HIV-inhibiting and autophagy inducing miRNA, may provide novel insights into the miRNA (small none-coding RNA)-mediated regulation of HIV inhibition and autophagy induction as an innate immune response. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Article
The Drosophila miR-959–962 Cluster Members Repress Toll Signaling to Regulate Antibacterial Defense during Bacterial Infection
Int. J. Mol. Sci. 2021, 22(2), 886; https://doi.org/10.3390/ijms22020886 - 17 Jan 2021
Cited by 2 | Viewed by 1125
Abstract
MicroRNAs (miRNAs) are a class of ~22 nt non-coding RNA molecules in metazoans capable of down-regulating target gene expression by binding to the complementary sites in the mRNA transcripts. Many individual miRNAs are implicated in a broad range of biological pathways, but functional [...] Read more.
MicroRNAs (miRNAs) are a class of ~22 nt non-coding RNA molecules in metazoans capable of down-regulating target gene expression by binding to the complementary sites in the mRNA transcripts. Many individual miRNAs are implicated in a broad range of biological pathways, but functional characterization of miRNA clusters in concert is limited. Here, we report that miR-959–962 cluster (miR-959/960/961/962) can weaken Drosophila immune response to bacterial infection evidenced by the reduced expression of antimicrobial peptide Drosomycin (Drs) and short survival within 24 h upon infection. Each of the four miRNA members is confirmed to contribute to the reduced Drs expression and survival rate of Drosophila. Mechanically, RT-qPCR and Dual-luciferase reporter assay verify that tube and dorsal (dl) mRNAs, key components of Toll pathway, can simultaneously be targeted by miR-959 and miR-960, miR-961, and miR-962, respectively. Furthermore, miR-962 can even directly target to the 3′ untranslated region (UTR) of Toll. In addition, the dynamic expression pattern analysis in wild-type flies reveals that four miRNA members play important functions in Drosophila immune homeostasis restoration at the late stage of Micrococcus luteus (M. luteus) infection. Taken together, our results identify four miRNA members from miR-959–962 cluster as novel suppressors of Toll signaling and enrich the repertoire of immune-modulating miRNA in Drosophila. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Article
Interferon-Mediated Long Non-Coding RNA Response in Macrophages in the Context of HIV
Int. J. Mol. Sci. 2020, 21(20), 7741; https://doi.org/10.3390/ijms21207741 - 19 Oct 2020
Cited by 5 | Viewed by 1058
Abstract
Interferons play a critical role in the innate immune response against a variety of pathogens, such as HIV-1. Recent studies have shown that long non-coding genes are part of a reciprocal feedforward/feedback relationship with interferon expression. They presumably contribute to the cell type [...] Read more.
Interferons play a critical role in the innate immune response against a variety of pathogens, such as HIV-1. Recent studies have shown that long non-coding genes are part of a reciprocal feedforward/feedback relationship with interferon expression. They presumably contribute to the cell type specificity of the interferon response, such as the phenotypic and functional transition of macrophages throughout the immune response. However, no comprehensive understanding exists today about the IFN–lncRNA interplay in macrophages, also a sanctuary for latent HIV-1. Therefore, we completed a poly-A+ RNAseq analysis on monocyte-derived macrophages (MDMs) treated with members of all three types of IFNs (IFN-α, IFN-ε, IFN-γ or IFN-λ) and on macrophages infected with HIV-1, revealing an extensive non-coding IFN and/or HIV-1 response. Moreover, co-expression correlation with mRNAs was used to identify important (long) non-coding hub genes within IFN- or HIV-1-associated gene clusters. This study identified and prioritized IFN related hub lncRNAs for further functional validation. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Review

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Review
A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs
Int. J. Mol. Sci. 2021, 22(17), 9535; https://doi.org/10.3390/ijms22179535 - 02 Sep 2021
Cited by 2 | Viewed by 1001
Abstract
Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of [...] Read more.
Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Review
Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors
Int. J. Mol. Sci. 2021, 22(17), 9259; https://doi.org/10.3390/ijms22179259 - 26 Aug 2021
Viewed by 1327
Abstract
Hepatitis E virus (HEV) usually causes self-limiting acute hepatitis, but the disease can become chronic in immunocompromised individuals. HEV infection in pregnant women is reported to cause up to 30% mortality, especially in the third trimester. Additionally, extrahepatic manifestations like neuronal and renal [...] Read more.
Hepatitis E virus (HEV) usually causes self-limiting acute hepatitis, but the disease can become chronic in immunocompromised individuals. HEV infection in pregnant women is reported to cause up to 30% mortality, especially in the third trimester. Additionally, extrahepatic manifestations like neuronal and renal diseases and pancreatitis are also reported during the course of HEV infection. The mechanism of HEV pathogenesis remains poorly understood. Innate immunity is the first line of defense triggered within minutes to hours after the first pathogenic insult. Growing evidence based on reverse genetics systems, in vitro cell culture models, and representative studies in animal models including non-human primates, has implicated the role of the host’s innate immune response during HEV infection. HEV persists in presence of interferons (IFNs) plausibly by evading cellular antiviral defense. This review summarizes our current understanding of recognizing HEV-associated molecular patterns by host cell Pattern Recognition Receptors (PRRs) in eliciting innate immune response during HEV infection as well as mechanisms of virus-mediated immune evasion. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Review
Role of Post-Translational Modifications of cGAS in Innate Immunity
Int. J. Mol. Sci. 2020, 21(21), 7842; https://doi.org/10.3390/ijms21217842 - 22 Oct 2020
Cited by 12 | Viewed by 1684
Abstract
Cyclic GMP–AMP synthase (cGAS) is the synthase that generates the second messenger cyclic GMP–AMP (cGAMP) upon DNA binding. cGAS was first discovered as the cytosolic DNA sensor that detects DNA exposed in the cytoplasm either from pathogens or cellular damage. Activated cGAS instigates [...] Read more.
Cyclic GMP–AMP synthase (cGAS) is the synthase that generates the second messenger cyclic GMP–AMP (cGAMP) upon DNA binding. cGAS was first discovered as the cytosolic DNA sensor that detects DNA exposed in the cytoplasm either from pathogens or cellular damage. Activated cGAS instigates the signaling cascades to activate type I interferon (IFN) expression, critical for host defense and autoimmune diseases. In addition, cGAS plays a role in senescence, DNA repair, apoptosis, and tumorigenesis. Recently, various post-translational modifications (PTMs) of cGAS have been reported, such as phosphorylation, ubiquitination, acetylation, glutamylation, and sumoylation. These PTMs profoundly affect cGAS functions. Thus, here we review the recent reported PTMs of cGAS and how these PTMs regulate cGAS enzymatic activity, DNA binding, and protein stability, and discuss the potential future directions. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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Review
A Role of Intracellular Toll-Like Receptors (3, 7, and 9) in Response to Mycobacterium tuberculosis and Co-Infection with HIV
Int. J. Mol. Sci. 2020, 21(17), 6148; https://doi.org/10.3390/ijms21176148 - 26 Aug 2020
Cited by 2 | Viewed by 1271
Abstract
Mycobacterium tuberculosis (Mtb) is a highly infectious acid-fast bacillus and is known to cause tuberculosis (TB) in humans. It is a leading cause of death from a sole infectious agent, with an estimated 1.5 million deaths yearly worldwide, and up to one third [...] Read more.
Mycobacterium tuberculosis (Mtb) is a highly infectious acid-fast bacillus and is known to cause tuberculosis (TB) in humans. It is a leading cause of death from a sole infectious agent, with an estimated 1.5 million deaths yearly worldwide, and up to one third of the world’s population has been infected with TB. The virulence and susceptibility of Mtb are further amplified in the presence of Human Immunodeficiency Virus (HIV). Coinfection with Mtb and HIV forms a lethal combination. Previous studies had demonstrated the synergistic effects of Mtb and HIV, with one disease accelerating the disease progression of the other through multiple mechanisms, including the modulation of the immune response to these two pathogens. The response of the endosomal pattern recognition receptors to these two pathogens, specifically toll-like receptors (TLR)-3, -7, and -9, has not been elucidated, with some studies producing mixed results. This article seeks to review the roles of TLR-3, -7, and -9 in response to Mtb infection, as well as Mtb-HIV-coinfection via Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing INF-β (TRIF)-dependent and myeloid differentiation factor 88 (MyD88)-dependent pathways. Full article
(This article belongs to the Special Issue DNA or RNA-Mediated Innate Immune Response)
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