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14 pages, 3711 KiB

Open AccessArticle

HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients

by Bingqing Zheng, Yating Yu, Zhaoyi Pan, Yujie Feng, Huajun Zhao, Qiuju Han and Jian Zhang

Int. J. Mol. Sci. 2021, 22(14), 7643; https://doi.org/10.3390/ijms22147643 - 16 Jul 2021

Cited by 11 | Viewed by 2847

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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20 pages, 2357 KiB

Open AccessArticle

Megalocytivirus Induces Complicated Fish Immune Response at Multiple RNA Levels Involving mRNA, miRNA, and circRNA

by Qian Wu, Xianhui Ning and Li Sun

Int. J. Mol. Sci. 2021, 22(6), 3156; https://doi.org/10.3390/ijms22063156 - 19 Mar 2021

Cited by 14 | Viewed by 2882

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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19 pages, 2315 KiB

Open AccessArticle

MicroRNA Profiles in Monocyte-Derived Macrophages Generated by Interleukin-27 and Human Serum: Identification of a Novel HIV-Inhibiting and Autophagy-Inducing MicroRNA

by Tomozumi Imamichi, Suranjana Goswami, Xiaojun Hu, Sylvain Laverdure, Jun Yang, Ju Qiu, Qian Chen, Brad T. Sherman and Weizhong Chang

Int. J. Mol. Sci. 2021, 22(3), 1290; https://doi.org/10.3390/ijms22031290 - 28 Jan 2021

Cited by 6 | Viewed by 2592

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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17 pages, 7756 KiB

Open AccessArticle

The Drosophila miR-959–962 Cluster Members Repress Toll Signaling to Regulate Antibacterial Defense during Bacterial Infection

by Ruimin Li, Xiaolong Yao, Hongjian Zhou, Ping Jin and Fei Ma

Int. J. Mol. Sci. 2021, 22(2), 886; https://doi.org/10.3390/ijms22020886 - 17 Jan 2021

Cited by 16 | Viewed by 3180

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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17 pages, 5160 KiB

Open AccessArticle

Interferon-Mediated Long Non-Coding RNA Response in Macrophages in the Context of HIV

by Tinus Schynkel, Matthew A. Szaniawski, Adam M. Spivak, Alberto Bosque, Vicente Planelles, Linos Vandekerckhove and Wim Trypsteen

Int. J. Mol. Sci. 2020, 21(20), 7741; https://doi.org/10.3390/ijms21207741 - 19 Oct 2020

Cited by 12 | Viewed by 3266

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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26 pages, 1128 KiB

Open AccessReview

A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs

by Yuhuai Xie and Yuanyuan Wei

Int. J. Mol. Sci. 2021, 22(17), 9535; https://doi.org/10.3390/ijms22179535 - 2 Sep 2021

Cited by 14 | Viewed by 4435

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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17 pages, 1330 KiB

Open AccessReview

Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors

by Pradip Devhare, Mridula Madiyal, Chiranjay Mukhopadhyay, Shiran Shetty and Shamee Shastry

Int. J. Mol. Sci. 2021, 22(17), 9259; https://doi.org/10.3390/ijms22179259 - 26 Aug 2021

Cited by 10 | Viewed by 4179

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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13 pages, 684 KiB

Open AccessReview

Role of Post-Translational Modifications of cGAS in Innate Immunity

by Yakun Wu and Shitao Li

Int. J. Mol. Sci. 2020, 21(21), 7842; https://doi.org/10.3390/ijms21217842 - 22 Oct 2020

Cited by 30 | Viewed by 6151

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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18 pages, 1290 KiB

Open AccessReview

A Role of Intracellular Toll-Like Receptors (3, 7, and 9) in Response to Mycobacterium tuberculosis and Co-Infection with HIV

by Huy Nguyen, Nicky Gazy and Vishwanath Venketaraman

Int. J. Mol. Sci. 2020, 21(17), 6148; https://doi.org/10.3390/ijms21176148 - 26 Aug 2020

Cited by 16 | Viewed by 4455

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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