scholarly journals RIG-I uses its intrinsically disordered CARDs-Helicase linker in RNA proofreading functions

2021 ◽  
Author(s):  
Brandon D. Schweibenz ◽  
Swapnil C. Devarkar ◽  
Mihai Solotchi ◽  
Jie Zhang ◽  
Bruce D. Pascal ◽  
...  
Keyword(s):  
Viral Infections ◽  
Innate Immune ◽  
Helicase Domain ◽  
First Line ◽  
Intrinsically Disordered ◽  
Gating Mechanism ◽  
Signaling Domain ◽  
Novel Target ◽  
Regulatory Functions ◽  
Crucial Part

AbstractThe innate immune receptor RIG-I provides the first line of defense against viral infections. Viral RNAs are recognized by the C-terminal domain (CTD) of RIG-I, but the RNA must engage the helicase domain to release the signaling domain CARDs from their autoinhibitory CARD2:Hel2i interactions. Because the helicase lacks RNA specificity, there must be mechanisms to proofread RNAs entering the helicase domain. Although such mechanisms are crucial in preventing aberrant immune responses by non-specific RNAs, they remain largely unknown. This study reveals a previously unknown proofreading mechanism that RIG-I uses to ensure the helicase engages RNAs chosen explicitly by the CTD. A crucial part of this mechanism involves the intrinsically disordered CARDs-Helicase Linker (CHL), which uses its negatively charged regions to electrostatically antagonize incoming RNAs. In addition to RNA gating, CHL is essential in stabilizing the CARD2:Hel2i interface. The CHL and CARD2:Hel2i interface work together, establishing a tunable gating mechanism that allows CTD-chosen RNAs to bind into the helicase while blocking non-specific RNAs. With its critical regulatory functions, CHL represents a novel target for RIG-I-based therapeutics.

scholarly journals Peptidoglycan O-Acetylation as a Virulence Factor: Its Effect on Lysozyme in the Innate Immune System

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 94 ◽  
Author(s):  
Ashley S. Brott ◽  
Anthony J. Clarke
Keyword(s):  
Immune System ◽  
Virulence Factor ◽  
Innate Immune System ◽  
Innate Immune ◽  
Host Immune System ◽  
Gram Negative Bacteria ◽  
First Line ◽  
Structural Support ◽  
Important Virulence Factor ◽  
Novel Target

The peptidoglycan sacculus of both Gram-positive and Gram-negative bacteria acts as a protective mesh and provides structural support around the entirety of the cell. The integrity of this structure is of utmost importance for cell viability and so naturally is the first target for attack by the host immune system during bacterial infection. Lysozyme, a muramidase and the first line of defense of the innate immune system, targets the peptidoglycan sacculus hydrolyzing the β-(1→4) linkage between repeating glycan units, causing lysis and the death of the invading bacterium. The O-acetylation of N-acetylmuramoyl residues within peptidoglycan precludes the productive binding of lysozyme, and in doing so renders it inactive. This modification has been shown to be an important virulence factor in pathogens such as Staphylococcus aureus and Neisseria gonorrhoeae and is currently being investigated as a novel target for anti-virulence therapies. This article reviews interactions made between peptidoglycan and the host immune system, specifically with respect to lysozyme, and how the O-acetylation of the peptidoglycan interrupts these interactions, leading to increased pathogenicity.

scholarly journals JAK-STAT Pathway: A Novel Target to Tackle Viral Infections

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2379
Author(s):  
Ifeanyi Jude Ezeonwumelu ◽  
Edurne Garcia-Vidal ◽  
Ester Ballana
Keyword(s):  
Viral Infections ◽  
Current Knowledge ◽  
Drug Repurposing ◽  
Innate Immune ◽  
Janus Kinase ◽  
Cellular Target ◽  
Proven Efficacy ◽  
Novel Target ◽  
Remarkable Progress ◽  
Stat Pathway

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.

scholarly journals Emerging Role of PYHIN Proteins as Antiviral Restriction Factors

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1464
Author(s):  
Matteo Bosso ◽  
Frank Kirchhoff
Keyword(s):  
Viral Infections ◽  
Specific Pattern ◽  
Immune Defense ◽  
Innate Immune ◽  
Cellular Proteins ◽  
Restriction Factors ◽  
First Line ◽  
Viral Pathogens ◽  
Molecular Patterns

Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures.

scholarly journals The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

2021 ◽  
Vol 48 (3) ◽  
pp. 2775-2789
Author(s):  
Ludwig Stenz
Keyword(s):  
Human Genome ◽  
Viral Infections ◽  
De Novo ◽  
Current Knowledge ◽  
Innate Immune ◽  
De Novo Mutation ◽  
Neuronal Diversity ◽  
Alu Sequences ◽  
Pol Iii ◽  
The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

scholarly journals Existence of natural mouse IgG mAbs recognising epitopes shared by malondialdehyde acetaldehyde adducts and Porphyromonas gingivalis

2021 ◽  
Vol 27 (2) ◽  
pp. 158-169
Author(s):  
Mikael Kyrklund ◽  
Heidi Kaski ◽  
Ramin Akhi ◽  
Antti E Nissinen ◽  
Outi Kummu ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Low Density Lipoprotein ◽  
Physiological Role ◽  
Density Lipoprotein ◽  
Tissue Homeostasis ◽  
Innate Immune ◽  
Periodontal Pathogen ◽  
First Line ◽  
Germline Genes ◽  
Innate Recognition

Natural Abs are produced by B lymphocytes in the absence of external Ag stimulation. They recognise self, altered self and foreign Ags, comprising an important first-line defence against invading pathogens and serving as innate recognition receptors for tissue homeostasis. Natural IgG Abs have been found in newborns and uninfected individuals. Yet, their physiological role remains unclear. Previously, no natural IgG Abs to oxidation-specific epitopes have been reported. Here, we show the cloning and characterisation of mouse IgG mAbs against malondialdehyde acetaldehyde (MAA)-modified low-density lipoprotein. Sequence analysis reveals high homology with germline genes, suggesting that they are natural. Further investigation shows that the MAA-specific natural IgG Abs cross-react with the major periodontal pathogen Porphyromonas gingivalis and recognise its principle virulence factors gingipain Kgp and long fimbriae. The study provides evidence that natural IgGs may play an important role in innate immune defence and in regulation of tissue homeostasis by recognising and removing invading pathogens and/or modified self-Ags, thus being involved in the development of periodontitis and atherosclerosis.

scholarly journals Special Issue: “Innate Immune Sensing of Viruses and Viral Evasion”

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 567
Author(s):  
Renate König ◽  
Carsten Münk
Keyword(s):  
Innate Immunity ◽  
Innate Immune ◽  
Special Issue ◽  
First Line ◽  
Review Articles ◽  
Immune Sensing ◽  
Innate Immune Sensing ◽  
Viral Evasion

In this Special Issue, a wide variety of original and review articles provide a timely overview of how viruses are recognized by and evade from cellular innate immunity, which represents the first line of defense against viruses [...]

scholarly journals Regulating Intracellular Antiviral Defense and Permissiveness to Hepatitis C Virus RNA Replication through a Cellular RNA Helicase, RIG-I

2005 ◽  
Vol 79 (5) ◽  
pp. 2689-2699 ◽  
Author(s):  
Rhea Sumpter ◽  
Yueh-Ming Loo ◽  
Eileen Foy ◽  
Kui Li ◽  
Mitsutoshi Yoneyama ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Infections ◽  
Cultured Cells ◽  
Rna Replication ◽  
Rna Helicase ◽  
Hcv Rna ◽  
Helicase Domain ◽  
Replication Studies ◽  
Virus Rna

ABSTRACT Virus-responsive signaling pathways that induce alpha/beta interferon production and engage intracellular immune defenses influence the outcome of many viral infections. The processes that trigger these defenses and their effect upon host permissiveness for specific viral pathogens are not well understood. We show that structured hepatitis C virus (HCV) genomic RNA activates interferon regulatory factor 3 (IRF3), thereby inducing interferon in cultured cells. This response is absent in cells selected for permissiveness for HCV RNA replication. Studies including genetic complementation revealed that permissiveness is due to mutational inactivation of RIG-I, an interferon-inducible cellular DExD/H box RNA helicase. Its helicase domain binds HCV RNA and transduces the activation signal for IRF3 by its caspase recruiting domain homolog. RIG-I is thus a pathogen receptor that regulates cellular permissiveness to HCV replication and, as an interferon-responsive gene, may play a key role in interferon-based therapies for the treatment of HCV infection.

scholarly journals Transcriptional Profiling and Functional Analysis of N1/N2 Neutrophils Reveal an Immunomodulatory Effect of S100A9-Blockade on the Pro-Inflammatory N1 Subpopulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Andreea C. Mihaila ◽  
Letitia Ciortan ◽  
Razvan D. Macarie ◽  
Mihaela Vadana ◽  
Sergiu Cecoltan ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Transcriptional Profiling ◽  
Innate Immune ◽  
Potential Contribution ◽  
Functional Differences ◽  
Elevated Expression ◽  
Pharmacological Blockade ◽  
Novel Target ◽  
Increased Activity ◽  
Homogenous Population

Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1 neutrophils were also characterized by elevated expression of NADPH oxidase subunits, as well as activation of the signaling molecules ERK and the p65 subunit of NF-kB. Moreover, we found that the S100A9 alarmin promotes the chemotactic and enzymatic activity of N1 neutrophils. S100A9 inhibition with a specific small-molecule blocker, reduced CCL2, CCL3 and CCL5 chemokine expression and decreased MPO and MMP-9 activity, by interfering with the NF-kB signaling pathway. Together, these findings reveal that N1 neutrophils are pro-inflammatory effectors of the innate immune response. Pharmacological blockade of S100A9 dampens the function of the pro-inflammatory N1 phenotype, promoting the alarmin as a novel target for therapeutic intervention in inflammatory diseases.

scholarly journals Prevailing role of mucosal immunoglobulins and B cells in teleost skin immune responses to bacterial infection

2020 ◽  
Author(s):  
Xiao-Ting Zhang ◽  
Yong-Yao Yu ◽  
Hao-Yue Xu ◽  
Zhen-Yu Huang ◽  
Xia Liu ◽  
...  
Keyword(s):  
B Cells ◽  
Bacterial Infection ◽  
Inflammatory Responses ◽  
The Body ◽  
Innate Immune ◽  
Flavobacterium Columnare ◽  
First Line ◽  
Skin Mucus ◽  
Skin Mucosa

AbstractThe skin of vertebrates is the outermost organ of the body and serves as the first line of defense against external aggressions. In contrast to mammalian skin, that of teleost fish lacks keratinization and has evolved to operate as a mucosal surface containing a skin-associated lymphoid tissue (SALT). Thus far, IgT representing the prevalent immunoglobulin (Ig) in SALT have only been reported upon infection with a parasite. However, very little is known about the types of B cells and Igs responding to bacterial infection in the teleost skin mucosa, as well as the inductive or effector role of the SALT in such responses. To address these questions, here we analyzed the immune response of trout skin upon infection with one of the most widespread fish skin bacterial pathogens, Flavobacterium columnare. This pathogen induced strong skin innate immune and inflammatory responses at the initial phases of infection. More critically, we found that the skin mucus of fish having survived the infection contained significant IgT-but not IgM- or IgD-specific titers against the bacteria. Moreover, we demonstrate the local proliferation and production of IgT+ B-cells and specific IgT titers respectively within the SALT upon bacterial infection. Thus, our findings represent the first demonstration that IgT is the main Ig isotype induced by the skin mucosa upon bacterial infection, and that because of the large surface of the skin, its SALT probably represents a prominent IgT inductive site in fish.

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