scholarly journals MicroRNA-181b-2 and MicroRNA-21-1 Negatively Regulate NF-κB and IRF3-Mediated Innate Immune Responses via Targeting TRIF in Teleost

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuena Sun ◽  
Lei Zhang ◽  
Ling Hong ◽  
Weiwei Zheng ◽  
Junxia Cui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Regulatory Networks ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Lower Vertebrates ◽  
Negative Role ◽  
Viral Components ◽  
Miichthys Miiuy

Upon recognition of bacterial or viral components by Toll-like receptors (TLRs), cells could be activated to induce a series of reactions to produce inflammatory cytokines, type I interferon (IFN), and IFN stimulating genes (ISG). MicroRNAs (miRNAs) are an important regulatory molecules that are widely involved in the regulatory networks of mammalian inflammation and immune responses; however, in lower vertebrates, the regulatory network of miRNA-mediated immune responses is poorly understood. Here, we report two miRNAs form Miichthys miiuy, namely, miR-181b-2 and miR-21-1, that play a negative role in host antiviral and antibacterial immunity. We found that miR-181b-2 and miR-21-1 are abundantly expressed in gram-negative bacteria, as well as RNA rhabdovirus infection. Inducible miR-181b-2 and miR-21-1 suppress the production of inflammatory cytokines and type I IFN by targeting TRIF, thereby avoiding excessive inflammation. We further revealed that miR-181b-2 and miR-21-1 modulate antibacterial and antiviral immunity through the TRIF-mediated NF-κB and IRF3 signaling pathways. The overall results indicate that miR-181b-2 and miR-21-1 act as negative feedback regulators and participate in host antibacterial and antiviral immune responses; this finding could provide information for a deeper understanding of the resistance of lower vertebrates to the invasion of pathogens and to avoidance of excessive immunity.

scholarly journals An Update on Innate Immune Responses during SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2060
Author(s):  
Yu Zhang ◽  
Shuaiyin Chen ◽  
Yuefei Jin ◽  
Wangquan Ji ◽  
Weiguo Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Type I Interferons ◽  
Organ Injury ◽  
Type I ◽  
Innate Immune Responses ◽  
Innate Immune Signaling ◽  
Viral Proteases ◽  
Viral Components ◽  
The Relationship

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family, which is responsible for the COVID-19 pandemic followed by unprecedented global societal and economic disruptive impact. The innate immune system is the body’s first line of defense against invading pathogens and is induced by a variety of cellular receptors that sense viral components. However, various strategies are exploited by SARS-CoV-2 to disrupt the antiviral innate immune responses. Innate immune dysfunction is characterized by the weak generation of type I interferons (IFNs) and the hypersecretion of pro-inflammatory cytokines, leading to mortality and organ injury in patients with COVID-19. This review summarizes the existing understanding of the mutual effects between SARS-CoV-2 and the type I IFN (IFN-α/β) responses, emphasizing the relationship between host innate immune signaling and viral proteases with an insight on tackling potential therapeutic targets.

scholarly journals Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Yu-Zhi Fu ◽  
Shan Su ◽  
Hong-Mei Zou ◽  
Yi Guo ◽  
Su-Yun Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Polymerase ◽  
Inflammatory Cytokines ◽  
Immune Evasion ◽  
Innate Immune ◽  
Transcriptional Level ◽  
Type I ◽  
Innate Immune Responses ◽  
Type I Ifns ◽  
Antiviral Genes

ABSTRACT Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-κB-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-κB to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level. IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

scholarly journals A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune response

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yinghua Zhao ◽  
Liyan Sui ◽  
Ping Wu ◽  
Wenfang Wang ◽  
Zedong Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Low Dose ◽  
Nuclear Translocation ◽  
Innate Immune ◽  
High Dose ◽  
Type I ◽  
Innate Immune Responses ◽  
N Protein

AbstractThe recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

scholarly journals SARS-CoV-2 nucleocapsid protein dually regulates innate immune responses

2021 ◽  
Author(s):  
Yinghua Zhao ◽  
Liyan Sui ◽  
Ping Wu ◽  
Wenfang Wang ◽  
Guangyun Tan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Low Dose ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Innate Immune ◽  
High Dose ◽  
Type I ◽  
Innate Immune Responses ◽  
N Protein

ABSTRACTThe recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and a cytokine storm in the late stage of infection, however, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein interacted with the tripartite motif protein 25 (TRIM25), thereby dually regulating the phosphorylation and nuclear translocation of IRF3, STAT1 and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress retinoic acid-inducible gene I (RIG-I) ubiquitination and activation. Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

scholarly journals The Sp1-Responsive microRNA-15b Negatively Regulates Rhabdovirus-Triggered Innate Immune Responses in Lower Vertebrates by Targeting TBK1

2021 ◽  
Vol 11 ◽  
Author(s):  
Renjie Chang ◽  
Qing Chu ◽  
Weiwei Zheng ◽  
Lei Zhang ◽  
Tianjun Xu
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune ◽  
Infection Model ◽  
Regulation Mechanism ◽  
Type I ◽  
Innate Immune Responses ◽  
Positive Role ◽  
Siniperca Chuatsi ◽  
Antiviral Immune Response

As is known to all, the production of type I interferon (IFN) plays pivotal roles in host innate antiviral immunity, and its moderate production play a positive role in promoting the activation of host innate antiviral immune response. However, the virus will establish a persistent infection model by interfering with the production of IFN, thereby evading the organism inherent antiviral immune response. Therefore, it is of great necessity to research the underlying regulatory mechanisms of type I IFN appropriate production under viral invasion. In this study, we report that a Sp1–responsive miR-15b plays a negative role in siniperca chuatsi rhabdovirus (SCRV)-triggered antiviral response in teleost fish. We found that SCRV could dramatically upregulate miiuy croaker miR-15b expression. Enhanced miR-15b could negatively regulate SCRV-triggered antiviral genes and inflammatory cytokines production by targeting TANK-binding kinase 1 (TBK1), thereby accelerating viral replication. Importantly, we found that miR-15b feedback regulates antiviral innate immune response through NF-κB and IRF3 signaling pathways. These findings highlight that miR-15b plays a crucial role in regulating virus–host interactions, which outlines a new regulation mechanism of fish’s innate immune responses.

scholarly journals Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Marta L. DeDiego ◽  
Luis Martinez-Sobrido ◽  
David J. Topham
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Kappa B ◽  
Virus Production ◽  
Innate Immune ◽  
Type I ◽  
Nuclear Factor ◽  
Innate Immune Responses ◽  
Virus Infections ◽  
Nuclear Factor Kappa ◽  
Ifn Treatment

ABSTRACT We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (IκB) kinase alpha (IKKα), IKKβ, and IKKε. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-κB) inhibitor (IκBα)-mediated phosphorylation by IKKε and IKKβ, respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication. IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKKα, IKKβ, and IKKε. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.

scholarly journals The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Longzhen He ◽  
Baocheng Wang ◽  
Yuanyuan Li ◽  
Leqing Zhu ◽  
Peiling Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

scholarly journals Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 821-834 ◽  
Author(s):  
Keqin Yan ◽  
Dingqing Feng ◽  
Jing Liang ◽  
Qing Wang ◽  
Lin Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Granulosa Cells ◽  
Innate Immune ◽  
Type I Interferons ◽  
Endocrine Function ◽  
Type I ◽  
Dna Sensor ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Ovarian Granulosa Cells

Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2′,5′-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting. Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro. The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.

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