The pharmacology of endosomal TLR agonists in viral disease

2007 ◽  
Vol 35 (6) ◽  
pp. 1468-1472 ◽  
Author(s):  
D.R. Averett ◽  
S.P. Fletcher ◽  
W. Li ◽  
S.E. Webber ◽  
J.R. Appleman
Keyword(s):  
Viral Disease ◽  
Therapeutic Benefit ◽  
Innate Immune ◽  
Clinical Effects ◽  
Tlr Agonists ◽  
Tlr7 Agonist ◽  
Interferon Induction ◽  
Natural Ligands ◽  
Clinical Profiles

The discovery of endosomal TLRs (Toll-like receptors) and their natural ligands has accelerated efforts to exploit them for therapeutic benefit. Importantly, this was preceded by clinical exploration of agents now known to be endosomal TLR agonists. Clinical effects in viral disease have been reported with agonists of TLR3, TLR7, TLR7/8 and TLR9, and the TLR7 agonist imiquimod is marketed for topical use against warts, a papillomavirus disease. The observed pre-clinical and clinical profiles of agonists of each of these TLRs suggest induction of a multifaceted innate immune response, with biomarker signatures indicative of type 1 interferon induction. However, these agents differ in both their pharmaceutical characteristics and the cellular distribution of their target TLRs, suggesting that drugs directed to these targets will display differences in their overall pharmacological profiles.

scholarly journals Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Chu ◽  
Chenhui Li ◽  
Yongxing Li ◽  
Qiuya Yu ◽  
Huansha Yu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Therapeutic Benefit ◽  
Perilla Frutescens ◽  
Innate Immune ◽  
Interferon Response ◽  
Innate Immune Responses ◽  
Simplex Virus

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.

scholarly journals Innate immune responses after stimulation with Toll-like receptor agonists in ex vivo microglial cultures and an in vivo model using mice with reduced microglia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
James A. Carroll ◽  
Brent Race ◽  
Katie Williams ◽  
James F. Striebel ◽  
Bruce Chesebro
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Ex Vivo ◽  
Innate Immune ◽  
Cpg Odn ◽  
Innate Immune Responses ◽  
Tlr Signaling ◽  
Tlr Agonists ◽  
Tlr7 Agonist

Abstract Background Past experiments studying innate immunity in the central nervous system (CNS) utilized microglia obtained from neonatal mouse brain, which differ developmentally from adult microglia. These differences might impact our current understanding of the role of microglia in CNS development, function, and disease. Methods Cytokine protein secretion was compared in ex vivo P3 and adult microglial cultures after exposure to agonists for three different toll-like receptors (TLR4, lipopolysaccharide [LPS]; TLR7, imiquimod [IMQ]; and TLR9, CpG Oligodeoxynucleotide [CpG-ODN] 1585). In addition, changes in inflammatory gene expression in ex vivo adult microglia in response to the TLR agonists was assessed. Furthermore, in vivo experiments evaluated changes in gene expression associated with inflammation and TLR signaling in brains of mice with or without treatment with PLX5622 to reduce microglia. Results Ex vivo adult and P3 microglia increased cytokine secretion when exposed to TLR4 agonist LPS and to TLR7 agonist IMQ. However, adult microglia decreased expression of numerous genes after exposure to TLR 9 agonist CpG-ODN 1585. In contrast, in vivo studies indicated a core group of inflammatory and TLR signaling genes increased when each of the TLR agonists was introduced into the CNS. Reducing microglia in the brain led to decreased expression of various inflammatory and TLR signaling genes. Mice with reduced microglia showed extreme impairment in upregulation of genes after exposure to TLR7 agonist IMQ. Conclusions Cultured adult microglia were more reactive than P3 microglia to LPS or IMQ exposure. In vivo results indicated microglial influences on neuroinflammation were agonist specific, with responses to TLR7 agonist IMQ more dysregulated in mice with reduced microglia. Thus, TLR7-mediated innate immune responses in the CNS appeared more dependent on the presence of microglia. Furthermore, partial responses to TLR4 and TLR9 agonists in mice with reduced microglia suggested other cell types in the CNS can compensate for their absence.

Covalent coupling of a novel TLR7 agonist to antigen elicits an effective immune response in a murine melanoma tumor model

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3019-3019
Author(s):  
G. A. Daniels ◽  
M. Chan ◽  
C. C. Wu ◽  
R. Tawatao ◽  
D. Messmer ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune ◽  
Primary Amines ◽  
Immune Stimulation ◽  
Melanoma Tumor ◽  
Tumor Challenge ◽  
Tlr Agonists ◽  
Covalent Coupling ◽  
Tlr7 Agonist ◽  
Chicken Ovalbumin

3019 Background: Toll-like receptor (TLR) signaling triggers innate immune stimulation capable of generating an adaptive immune response under appropriate conditions. TLR agonists have shown efficacy in preclinical and clinical cancer therapies. However, one limitation to this approach has been the use of TLR agonists delivered at distances away from the target (ie-subcutaneous injections for general immune stimulation) or the inability to effectively couple antigen with adjuvant. Methods: We have synthesized a novel TLR7 agonist capable of covalent coupling to primary amines under physiologic conditions. In vitro activity of adjuvant alone or antigen-adjuvant complexes were tested for innate immune activation by utilizing bone marrow-derived murine or peripheral blood mononuclear cell-derived dendritic cells (DC) with respect to DC maturation and cytokine secretion (IL12, IL6, TGFbeta and IFNgamma). Immunocompetent syngeneic C57/b6 mice were prophylactically vaccinated with intradermal with either antigen, antigen mixed with adjuvant or antigen- adjuvant coupled complexes and challenged with B16 melanoma tumor cells expressing the cOVA transgene. Results: The effective concentration (EC50) for each compound generally followed a bell shaped distribution with higher doses being inhibitory. Maximal stimulation occurred between 10 and 1000nM. Coupled adjuvant molecules retained activity with generally lower EC50 values. Coupling 1V199 to chicken ovalbumin nearly doubled median survival from 22 to 35 days following subcutaneous tumor challenge compared with chicken ovalbumin alone. Conclusions: Covalent linkage of a TLR7 agonist to antigen stimulates DC cytokine production and protects mice from tumor challenge. Use of a soluble TLR7 agonist which retains its immune stimulating properties following coupling to antigen under physiologic conditions may be useful in the development of an in situ vaccine in solid tumor therapy. No significant financial relationships to disclose.

Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
MP Ashton ◽  
I Tan ◽  
L Mackin ◽  
C Elso ◽  
E Chu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Hepatitis C Virus Infection Is Inhibited by a Noncanonical Antiviral Signaling Pathway Targeted by NS3-NS4A

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Christine Vazquez ◽  
Chin Yee Tan ◽  
Stacy M. Horner
Keyword(s):  
Hepatitis C ◽  
Viral Replication ◽  
Signaling Pathway ◽  
Transmembrane Domain ◽  
Innate Immune ◽  
Hcv Infection ◽  
Interferon Induction ◽  
Innate Immune Signaling ◽  
Huh7 Cells ◽  
Irf3 Activation

ABSTRACT The hepatitis C virus (HCV) NS3-NS4A protease complex is required for viral replication and is the major viral innate immune evasion factor. NS3-NS4A evades antiviral innate immunity by inactivating several proteins, including MAVS, the signaling adaptor for RIG-I and MDA5, and Riplet, an E3 ubiquitin ligase that activates RIG-I. Here, we identified a Tyr-16-Phe (Y16F) change in the NS4A transmembrane domain that prevents NS3-NS4A targeting of Riplet but not MAVS. This Y16F substitution reduces HCV replication in Huh7 cells, but not in Huh-7.5 cells, known to lack RIG-I signaling. Surprisingly, deletion of RIG-I in Huh7 cells did not restore Y16F viral replication. Rather, we found that Huh-7.5 cells lack Riplet expression and that the addition of Riplet to these cells reduced HCV Y16F replication, whereas the addition of Riplet lacking the RING domain restored HCV Y16F replication. In addition, TBK1 inhibition or IRF3 deletion in Huh7 cells was sufficient to restore HCV Y16F replication, and the Y16F protease lacked the ability to prevent IRF3 activation or interferon induction. Taken together, these data reveal that the NS4A Y16 residue regulates a noncanonical Riplet-TBK1-IRF3-dependent, but RIG-I-MAVS-independent, signaling pathway that limits HCV infection. IMPORTANCE The HCV NS3-NS4A protease complex facilitates viral replication by cleaving and inactivating the antiviral innate immune signaling proteins MAVS and Riplet, which are essential for RIG-I activation. NS3-NS4A therefore prevents IRF3 activation and interferon induction during HCV infection. Here, we uncover an amino acid residue within the NS4A transmembrane domain that is essential for inactivation of Riplet but does not affect MAVS cleavage by NS3-NS4A. Our study reveals that Riplet is involved in a RIG-I- and MAVS-independent signaling pathway that activates IRF3 and that this pathway is normally inactivated by NS3-NS4A during HCV infection. Our study selectively uncouples these distinct regulatory mechanisms within NS3-NS4A and defines a new role for Riplet in the antiviral response to HCV. Since Riplet is known to be inhibited by other RNA viruses, such as such influenza A virus, this innate immune signaling pathway may also be important in controlling other RNA virus infections.

scholarly journals Susceptibility to Polyomavirus-Induced Tumors in Inbred Mice: Role of Innate Immune Responses

2002 ◽  
Vol 76 (19) ◽  
pp. 9657-9663 ◽  
Author(s):  
Palanivel Velupillai ◽  
John P. Carroll ◽  
Thomas L. Benjamin
Keyword(s):  
Antigen Presenting Cells ◽  
Interleukin 10 ◽  
Cytokine Response ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Cytokine Responses ◽  
Induced Tumors ◽  
Antigen Presenting ◽  
Type 1 Cytokine

ABSTRACT Mice of the PERA/Ei strain (PE mice) are highly susceptible to tumor induction by polyomavirus and transmit their susceptibility in a dominant manner in crosses with resistant C57BR/cdJ mice (BR mice). BR mice respond to polyomavirus infection with a type 1 cytokine response and develop effective cell-mediated immunity to the virus-induced tumors. By enumerating virus-specific CD8+ T cells and measuring cytokine responses, we show that the susceptibility of PE mice is due to the absence of a type 1 cytokine response and a concomitant failure to sustain virus-specific cytotoxic T lymphocytes. (PE × BR)F1 mice showed an initial type 1 response that became skewed toward type 2. Culture supernatants of splenocytes from infected PE mice stimulated in vitro contained high levels of interleukin-10 and no detectable gamma interferon, while those from BR mice showed the opposite pattern. Differences in the innate immune response to polyomavirus by antigen-presenting cells in PE mice and BR mice led to polarization of T-cell cytokine responses. Adherent cells from spleens of infected BR mice produced high levels of interleukin-12, while those from infected PE and F1 mice produced predominantly interleukin-10. PE and F1 mice infected by polyomavirus responded with increases in antigen-presenting cells expressing B7.2 costimulatory molecules, whereas BR mice responded with increased expression of B7.1. Administration of recombinant interleukin-12 along with virus resulted in partial protection of PE mice and provided complete protection against tumor development in F1 animals.

scholarly journals Innate immune-mediated antiviral response to SARS-CoV-2 and convalescent sera a potential prophylactic and therapeutic agent to tackle COVID-19

2020 ◽  
Vol 3 (3) ◽  
pp. 212-220
Author(s):  
Abdullah ◽  
Shah Faisal ◽  
Komal Aman ◽  
Anees ur Rahman
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Alveolar Cells ◽  
Experimental Drugs ◽  
Immune Mediated

ABSTRACT The whole world is confronting the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, there is no vaccine to prevent novel coronavirus infection. Besides several experimental drugs, the strong immune responses and convalescent sera are the current two potential options to tackle coronavirus disease 2019 (COVID-19) infection. Innate immune-mediated antiviral responses are initiated by the recognition of viral invasion through pathogen-associated molecular patterns (PAMPs). In coronavirus, the PAMPs are recognized by Toll-like receptors 3 and 7, endosomal ribonucleic acid receptors, RNA in cytosol, and by pattern recognition receptor (RIG-1) in the alveolar cells and site of invasion. Nuclear factor-κB and interferon regulatory transcription factor (IRF3) are activated in response to the above recognition episode and translocate to nucleus. These transcription factors in the nucleus initiate the expression of interferon type 1 and pro-inflammatory cytokine storm, which leads to first line of defense at the site of viral entrance. The effectiveness of innate immune system is greatly relies on type 1 interferons and its cascade, because of their role in the inhibition of viral replication and initiation of adaptive immune responses. The successful interferon type 1 response put down the viral replication and transmission at prompt point. Passive immunization is the administering of antibodies into infected patients, which is taken from recovered individuals. The convalescent sera of the recovered COVID-19 patients are containing antiviral neutralizing antibodies and are used therapeutically for infected individuals by SARS-CoV-2 and for the purpose of prophylaxis in exposed individuals. The convalescent sera is found effective when administered early at the onset of symptoms.

scholarly journals Microbiota regulates type 1 diabetes through Toll-like receptors

2015 ◽  
Vol 112 (32) ◽  
pp. 9973-9977 ◽  
Author(s):  
Michael P. Burrows ◽  
Pavel Volchkov ◽  
Koichi S. Kobayashi ◽  
Alexander V. Chervonsky
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Intestinal Bacteria ◽  
Primary Response ◽  
Innate Immune ◽  
Specific Pathogen ◽  
Immune Sensing ◽  
Critical Components ◽  
Innate Immune Sensing

Deletion of the innate immune adaptor myeloid differentiation primary response gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) results in microbiota-dependent protection from the disease: MyD88-negative mice in germ-free (GF), but not in specific pathogen-free conditions develop the disease. These results could be explained by expansion of particular protective bacteria (“specific lineage hypothesis”) or by dominance of negative (tolerizing) signaling over proinflammatory signaling (“balanced signal hypothesis”) in mutant mice. Here we found that colonization of GF mice with a variety of intestinal bacteria was capable of reducing T1D in MyD88-negative (but not wild-type NOD mice), favoring the balanced signal hypothesis. However, the receptors and signaling pathways involved in prevention or facilitation of the disease remained unknown. The protective signals triggered by the microbiota were revealed by testing NOD mice lacking MyD88 in combination with knockouts of several critical components of innate immune sensing for development of T1D. Only MyD88- and TIR-domain containing adapter inducing IFN β (TRIF) double deficient NOD mice developed the disease. Thus, TRIF signaling (likely downstream of Toll-like receptor 4, TLR4) serves as one of the microbiota-induced tolerizing pathways. At the same time another TLR (TLR2) provided prodiabetic signaling by controlling the microbiota, as reduction in T1D incidence caused by TLR2 deletion was reversed in GF TLR2-negative mice. Our results support the balanced signal hypothesis, in which microbes provide signals that both promote and inhibit autoimmunity by signaling through different receptors, including receptors of the TLR family.

scholarly journals Old World hantaviruses do not produce detectable amounts of dsRNA in infected cells and the 5′ termini of their genomic RNAs are monophosphorylated

2011 ◽  
Vol 92 (5) ◽  
pp. 1199-1204 ◽  
Author(s):  
Hao Wang ◽  
Antti Vaheri ◽  
Friedemann Weber ◽  
Alexander Plyusnin
Keyword(s):  
Rna Virus ◽  
Innate Immune ◽  
Hantaan Virus ◽  
Signalling Pathways ◽  
Genomic Rna ◽  
Genomic Rnas ◽  
Old World ◽  
Interferon Induction ◽  
Infected Cells ◽  
Negative Sense

dsRNA and 5′-triphosphate RNA are considered critical activators of the innate immune response because of their interaction with pattern recognition receptors. It has been reported that no dsRNA is detected in negative-sense RNA virus-infected cells and that Hantaan virus (HTNV) genomic RNA bears a 5′ monophosphate group. In this paper we examine the 5′ termini of genomic RNAs of and dsRNA production by two major groups of Old World hantaviruses. No detectable amounts of dsRNA were found in infected cells. Also, the genomic RNAs of these hantaviruses bear a 5′ monophosphate group and therefore are unable to trigger interferon induction. Taken together with the earlier data on HTNV, these results suggest that in addition to the dsRNA and genomic RNA, which may be only minimally involved in the induction of innate immunity, other cellular signalling pathways may also be involved and that these await further investigation.

scholarly journals TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients

2020 ◽  
Vol 99 (1) ◽  
pp. 147-158
Author(s):  
L. Dold ◽  
L. Zimmer ◽  
C. Schwarze-Zander ◽  
C. Boesecke ◽  
R. Mohr ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Double Positive ◽  
Hiv Patients ◽  
Ifn Gamma ◽  
Tlr Agonists

Abstract HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14+CD16++ monocytes as well as IFN-gamma-positive cytotoxic CD56highCD16neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. Key messages • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands.

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