scholarly journals Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment

2021 ◽  
Author(s):  
Kensuke Miyake ◽  
Shin-ichiroh Saitoh ◽  
Ryutaro Fukui ◽  
Takuma Shibata ◽  
Ryota Sato ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Degradation Products ◽  
Proteolytic Cleavage ◽  
Innate Immune ◽  
Cell Periphery ◽  
Type I ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Endosomal Compartment

Abstract Nucleic acid (NA)-sensing Toll-like receptors (TLRs) are synthesized in the endoplasmic reticulum and mature with chaperones, such as Unc93B1 and the protein associated with TLR4 A (PRAT4A)–gp96 complex. The TLR–Unc93B1 complexes move to the endosomal compartment, where proteases such as cathepsins activate their responsiveness through proteolytic cleavage of the extracellular domain of TLRs. Without proteolytic cleavage, ligand-dependent dimerization of NA-sensing TLRs is prevented by the uncleaved loop in the extracellular domains. Additionally, the association of Unc93B1 inhibits ligand-dependent dimerization of TLR3 and TLR9 and, therefore, Unc93B1 is released from these TLRs before dimerization. Ligand-activated NA-sensing TLRs induce the production of proinflammatory cytokines and act on the endosomal compartment to initiate anterograde trafficking to the cell periphery for type I interferon production. In the endosomal compartment, DNA and RNA are degraded by DNases and RNases, respectively, generating degradation products. DNase 2A and RNase T2 generate ligands for TLR9 and TLR8, respectively. In this mechanism, DNases and RNases control innate immune responses to NAs in endosomal compartments. NA-sensing TLRs and the endosomal compartment work together to monitor environmental cues through endosomes and decide to launch innate immune responses.

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.

Phase II Trial of a Toll-Like Receptor 9–Activating Oligonucleotide in Patients With Metastatic Melanoma

2006 ◽  
Vol 24 (36) ◽  
pp. 5716-5724 ◽  
Author(s):  
Mikhail Pashenkov ◽  
Gerda Goëss ◽  
Christine Wagner ◽  
Markus Hörmann ◽  
Tamara Jandl ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase Ii ◽  
Killer Cell ◽  
Pilot Trial ◽  
Surrogate Marker ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Natural Killer Cell Cytotoxicity ◽  
Stimulation Of

Purpose The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) –activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients. Patients and Methods Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors. Results Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. Laboratory and nonlaboratory adverse events were limited, transient, and did not result in any withdrawals. Two patients experienced a confirmed partial response; one response is ongoing for 140+ weeks. Three patients experienced stable disease. Immunologic measurements revealed induction of an activated phenotype of PDC, elevation of serum levels of 2′,5′-oligoadenylate, a surrogate marker of type I interferon production, and significant stimulation of natural killer cell cytotoxicity (the latter was associated with clinical benefit). Conclusion These results indicate that TLR9-targeted therapy can stimulate innate immune responses in cancer patients, identify biomarkers that may be associated with TLR9-induced tumor regression, and encourage the design of follow-up studies to evaluate the ability of this therapeutic approach to target human cancer.

scholarly journals CD14 is a coreceptor of Toll-like receptors 7 and 9

2010 ◽  
Vol 207 (12) ◽  
pp. 2689-2701 ◽  
Author(s):  
Christoph L. Baumann ◽  
Irene M. Aspalter ◽  
Omar Sharif ◽  
Andreas Pichlmair ◽  
Stephan Blüml ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Innate Immune ◽  
Confocal Imaging ◽  
Acid Uptake ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Molecular Patterns ◽  
Cluster Of Differentiation

Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid–mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.

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