scholarly journals Toll-Like Receptors and their Contribution to Innate Immunity: Focus on TLR4 Activation by Lipopolysaccharide

2014 ◽  
Vol 4 (1) ◽  
pp. 1-23 ◽  
Author(s):  
Maciej Czerkies ◽  
Katarzyna Kwiatkowska
Keyword(s):  
Innate Immunity ◽  
Ligand Binding ◽  
Transmembrane Domain ◽  
Adaptor Proteins ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptors ◽  
Signalling Cascades ◽  
Genes Encoding ◽  
Membrane Components

Summary Mechanisms of innate immunity are triggered as a result of recognition of evolutionarily conserved structures of microorganisms, named pathogen-associated molecular patterns. Their recognition is mediated by specialized receptors which initiate signalling cascades leading to expression of pro-inflammatory mediators and regulation of acquired immunity. Among several classes of such receptors, Toll-like receptors (TLRs) are extensively studied as they can sense an array of microbial cell wall and membrane components as well as single- and double-stranded RNA and DNA motifs typical for microorganisms. Each TLR consists of a ligand-binding domain containing leucine-rich repeats, a single transmembrane domain and a signalling TIR domain. After ligand binding, TLRs dimerize which facilitates the interaction of their TIR domains with adaptor proteins triggering signalling cascades. TLRs engage four common adaptor proteins, about ten signalling kinases, and a few transcription factors including NFκB, IRF and AP-1. In this review, special attention is paid to TLR4 activated by lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, since an exaggerated response to LPS may lead to potentially deadly septic shock. In recent years considerable progress has been made in the understanding of how the cooperation of several proteins, including CD14, TLR4/MD-2 complex and scavenger receptors, modulates the cell response to LPS. These studies have also revealed a dichotomy of signalling pathways triggered by TLR4 which depends on the participation of MyD88 and TRIF adaptor proteins and leads to the expression of genes encoding pro-inflammatory cytokines and type I interferons, respectively. The key event in the TRIF-dependent pathway is the internalization of activated TLR4.

The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria

2009 ◽  
Vol 5 (2) ◽  
pp. 143-149
Author(s):  
Marja Ojaniemi ◽  
Mari Liljeroos ◽  
Reetta Vuolteenaho
Keyword(s):  
Type I Interferons ◽  
Host Responses ◽  
Type I ◽  
Toll Like Receptors

scholarly journals Route of Infection Determines the Impact of Type I Interferons on Innate Immunity to Listeria monocytogenes

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65007 ◽  
Author(s):  
Elisabeth Kernbauer ◽  
Verena Maier ◽  
Isabella Rauch ◽  
Mathias Müller ◽  
Thomas Decker
Keyword(s):  
Innate Immunity ◽  
Listeria Monocytogenes ◽  
Type I Interferons ◽  
Type I ◽  
Route Of Infection ◽  
The Impact

scholarly journals Role of Toll-like Receptors in Adjuvant-Augmented Immune Therapies

2006 ◽  
Vol 3 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Tsukasa Seya ◽  
Takashi Akazawa ◽  
Tadayuki Tsujita ◽  
Misako Matsumoto
Keyword(s):  
Type I Interferons ◽  
Target Cells ◽  
Type I ◽  
Toll Like Receptors ◽  
Myeloid Dendritic Cells ◽  
Therapeutic Vaccines ◽  
Adjuvant Activity ◽  
Host Immune Responses

Effective therapeutic vaccines contain two primary constituents, antigen and adjuvant. Adjuvants consisting of microbial pattern molecules play a central role in vaccination. Successful vaccine requires efficient induction of antibody (Ab), type I interferons (IFN), cytokines/chemokines, cytotoxic T lymphocytes (CTL) and/or NK cells. Toll-like receptors (TLRs) in myeloid dendritic cells (mDC) essentially act as adjuvant receptors and sustain the molecular basis of adjuvant activity. Current consensus is that TLRs and their adapters introduce signals to preferentially induce IFN-α/β, chemokines and proinflammatory cytokines, and mature mDC to augment antigen presentation. Although most of these data were obtained with mice, the results are presumed to be adaptable to humans. Whenever TLR pathway is activated in mDC, NK and/or CTL activation is promoted. For induction of antigen-specific CTL toward phagocytosed material, cross-priming must be induced in mDC, which is also sustained by TLR signaling in mDC. Since the TLR responses vary with different adjuvants, mDC functions are skewed depending on adjuvant-specific direction of mDC maturation. It appears that the directed maturation of mDC largely relies on selection of appropriate sets of TLRs and their adapter signaling pathways. Synthetic chimera molecules consisting of TLR agonists and target antigens are found to be effective in induction of CTL to eliminate target cellsin vivo. Here, we review the role of human TLRs and adapters in a variety of host immune responses. We will also describe the relevance of adjuvants in the manipulation of receptors and adapters in vaccine therapy.

scholarly journals Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Jintao Zhang ◽  
Chunyuan Zhao ◽  
Wei Zhao
Keyword(s):  
Innate Immunity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Responses ◽  
Public Health Challenges ◽  
Host Innate Immunity ◽  
Efficient Elimination

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.

scholarly journals Extensive evolutionary and functional diversity among mammalian AIM2-like receptors

2012 ◽  
Vol 209 (11) ◽  
pp. 1969-1983 ◽  
Author(s):  
Rebecca L. Brunette ◽  
Janet M. Young ◽  
Deborah G. Whitley ◽  
Igor E. Brodsky ◽  
Harmit S. Malik ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Phylogenetic Analysis ◽  
Gene Family ◽  
Functional Diversity ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Responses ◽  
Immune Detection ◽  
Dependent Type

Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.

scholarly journals When human guanylate-binding proteins meet viral infections

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Rongzhao Zhang ◽  
Zhixin Li ◽  
Yan-Dong Tang ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Downstream Signaling ◽  
Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

scholarly journals The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium

2021 ◽  
Author(s):  
Luke R. Bonser ◽  
Walter L. Eckalbar ◽  
Lauren Rodriguez ◽  
Jiangshan Shen ◽  
Kyung Duk Koh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Airway Epithelium ◽  
Limit Of Detection ◽  
Bronchial Epithelium ◽  
Type I Interferons ◽  
Chronic Obstructive ◽  
Type I ◽  
Obstructive Pulmonary Disease ◽  
Genes Encoding

AbstractRationaleAsthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown.ObjectivesWe sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection.MethodsWe used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs.Measurements and Main ResultsTranscripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection.ConclusionsIL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.

scholarly journals MicroRNA-122 supports robust innate immunity in hepatocytes by suppressing STAT3 phosphorylation

2018 ◽  
Author(s):  
Hui Xu ◽  
Shi-Jun Xu ◽  
Shu-Juan Xie ◽  
Yin Zhang ◽  
Jian-Hua Yang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tyrosine Kinases ◽  
Large Scale ◽  
Type I Interferons ◽  
Poly I:C ◽  
Hcv Rna ◽  
Type I ◽  
Type Iii ◽  
Stat3 Phosphorylation ◽  
Potential Strategy

ABSTRACTThe intrinsic innate immunity of hepatocytes is essential for the control of hepatitis viruses and influences the outcome of antiviral therapy. MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and is a central player in liver biology and disease. However, little is known about the role of miR-122 in hepatocyte innate immunity. Herein, we show that restoring miR-122 levels in hepatoma cells markedly increased the activation of both type III and type I interferons (IFNs) in response to hepatitis C virus (HCV) RNA or poly(I:C). We determined that miR-122 promotes IFN production through down-regulating the tyrosine (Tyr705) phosphorylation of STAT3. We show that STAT3 represses IFN activation by inhibiting interferon regulatory factor 1 (IRF1), which is rate-limiting for maximal IFN expression, especially type III IFNs. Through large-scale screening, we identified that miR-122 targets MERTK, FGFR1 and IGF1R, three oncogenic receptor tyrosine kinases that directly promote STAT3 phosphorylation. These findings reveal a previously unknown role for miR-122 in hepatic immunity and indicate a new potential strategy for treating hepatic infections through targeting STAT3.

scholarly journals Role of Super Immune Activation Secondary to Infection in the Context of Cancer

2021 ◽  
Vol 01 (10) ◽  
Author(s):  
Javier Contreras Cardenas ◽  
Keyword(s):  
Innate Immunity ◽  
Risk Factor ◽  
Tumor Suppressor Genes ◽  
Nk Cell ◽  
Epigenetic Modification ◽  
Type I Interferons ◽  
Type I ◽  
Pathophysiological Mechanism ◽  
Infected Cells

By 2008, it was estimated that there were about 12.7 million new cases of cancer worldwide, resulting in 7.6 million deaths. We are aware of the heterogeneity that exists and that it is impossible to link its development in any organ to a single pathophysiological mechanism. The greatest risk factor for developing cancer is aging, as age is directly proportional to accumulated aberrations and exposure to carcinogens. Most cancers occur in people who have no overt immunodeficiency. It is evident, then, that tumor cells must develop mechanisms to escape or evade the immune system in immunocompetent hosts. The main mechanisms of innate immunity against viruses are inhibition of infection by type I interferons and NK cell-mediated death of infected cells. The hypothesis is that perhaps the ability of epigenetic modification, which varies from virus to virus, is not exclusively reduced to the ability to activate genes that lead to cancer; but also randomly empower the organism to activate tumor suppressor genes.

Functional Analysis of Leukemia-Associated Mutations Involving the Heterodimerization Domain of NOTCH1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 843-843
Author(s):  
Cheryll Sanchez-Irizarry ◽  
Michael Malecki ◽  
Woojoong Lee ◽  
Mina Xu ◽  
Stephen C. Blacklow ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Reporter Gene ◽  
Cleavage Site ◽  
Transmembrane Domain ◽  
Regulatory Region ◽  
Receptor Activation ◽  
Luciferase Reporter ◽  
Type I ◽  
Gamma Secretase ◽  
Gain Of Function

Abstract NOTCH1 is a type I transmembrane receptor that regulates T cell development via a signaling pathway that relies on regulated proteolysis. During its maturation, most NOTCH1 is cleaved at a position 70 amino acids external to the transmembrane domain by a furin-like protease, creating extracellular (NEC) and transmembrane (NTM) subunits that are held together non-covalently by a juxtamembranous heterodimerization (HD) domain. Ligand-binding to NEC promotes cleavage by i) metalloproteases at a site in the ectodomain of NTM, followed by ii) gamma-secretase within the transmembrane domain. This releases the NOTCH1 intracellular domain (ICN1), allowing it to translocate to the nucleus and activate target genes. Normally, proteolysis is constrained prior to ligand-binding by an extracellular negative regulatory region consisting of 3 iterated LNR repeats and the N- and C-terminal portions of the HD domain, which flank the furin cleavage site. Recent work has shown that human T-ALL is frequently associated with gain of function mutations that map to the HD domain of NOTCH1. These mutations are distributed in both parts of the HD domain and include point mutations, short insertions, and deletions, suggesting that there might be variation in their relative strength and the mechanisms by which they act. To investigate these issues, we introduced 16 of the HD domain mutations found in primary T-ALLs or T-ALL cell lines into a full-length NOTCH1 cDNA, and tested their ability to activate a NOTCH sensitive luciferase reporter gene. Except for the "mutation" R1609S, which was found in only one primary T-ALL sample, all of the mutations stimulated NOTCH1 signaling. These increases in signaling were abolished by a gamma-secretase inhibitor and were associated with increased rates of metalloprotease-mediated cleavage, indicating that activation proceeds through the normal series of proteolytic events. The mutations also caused gains in function when introduced into NOTCH1 polypeptides lacking the ligand-binding region of NEC, indicating that the HD domain mutations can cause ligand-independent receptor activation. Since NEC dissociation can lead to activation of NOTCH signaling (and is a proposed mechanism for normal ligand-mediated NOTCH activation), one simple way for HD domain mutations to act is through the destabilization of NOTCH1 heterodimers. To test this model, each mutation was introduced into soluble NOTCH1 mini-receptors bearing N-terminal FLAG and C-terminal HA tags. When expressed transiently, the normal NOTCH1 mini-receptor was secreted into conditioned media as a furin-processed heterodimer. Certain activating HD domain mutations, such as L1601P, resulted in complete dissociation of the furin-processed mini-receptor subunits under native conditions, and all other HD domain mutations save one were more sensitive to urea-induced dissociation than normal NOTCH1. The exception was an unusual insertional mutation (identified in the P12-Ichikawa cell line) that introduces a 14 amino acid direct repeat sequence at a position immediately N-terminal of the metalloprotease cleavage site. We hypothesize that this mutation, which was associated with the greatest increases in signaling in NOTCH1 reporter gene assays, displaces protective HD and LNR domain residues and thereby unveils the metalloprotease cleavage site. We conclude that most T-ALL-associated HD domain mutations confer ligand-independent gain-of-function on NOTCH1 receptors, but vary in strength and are likely to act through several distinct mechanisms.

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