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 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 Canonical and Noncanonical Autophagy as Potential Targets for COVID-19

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1619 ◽  
Author(s):  
Melissa Bello-Perez ◽  
Isabel Sola ◽  
Beatriz Novoa ◽  
Daniel J. Klionsky ◽  
Alberto Falco
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Innate Immune ◽  
Interacting Proteins ◽  
Innate Immune Responses ◽  
Molecular Machinery ◽  
Autophagy Pathway

The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.

scholarly journals The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 758 ◽  
Author(s):  
Karim Majzoub ◽  
Florian Wrensch ◽  
Thomas F. Baumert
Keyword(s):  
Viral Infections ◽  
Current Knowledge ◽  
Innate Immune ◽  
Model Organisms ◽  
Animal Cells ◽  
Molecular Systems ◽  
Host Interactions ◽  
Animal Hosts ◽  
Immune Pathways ◽  
Innate Antiviral Response

Animal cells have evolved dedicated molecular systems for sensing and delivering a coordinated response to viral threats. Our understanding of these pathways is almost entirely defined by studies in humans or model organisms like mice, fruit flies and worms. However, new genomic and functional data from organisms such as sponges, anemones and mollusks are helping redefine our understanding of these immune systems and their evolution. In this review, we will discuss our current knowledge of the innate immune pathways involved in sensing, signaling and inducing genes to counter viral infections in vertebrate animals. We will then focus on some central conserved players of this response including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and cGAS-STING, attempting to put their evolution into perspective. To conclude, we will reflect on the arms race that exists between viruses and their animal hosts, illustrated by the dynamic evolution and diversification of innate immune pathways. These concepts are not only important to understand virus-host interactions in general but may also be relevant for the development of novel curative approaches against human disease.

scholarly journals The JAK/STAT signaling pathway: from bench to clinic

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaoyi Hu ◽  
Jing li ◽  
Maorong Fu ◽  
Xia Zhao ◽  
Wei Wang
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Quarter Century ◽  
Cellular Processes ◽  
Stat Signaling ◽  
Cancer And Inflammation ◽  
Stat Pathway

AbstractThe Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

scholarly journals Phagocytosis, Degranulation and Extracellular Traps Release by Neutrophils—The Current Knowledge, Pharmacological Modulation and Future Prospects

2021 ◽  
Vol 12 ◽  
Author(s):  
Barbara Gierlikowska ◽  
Albert Stachura ◽  
Wojciech Gierlikowski ◽  
Urszula Demkow
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Current Knowledge ◽  
Innate Immune ◽  
Therapeutic Approaches ◽  
Effector Functions ◽  
Pharmacological Modulation ◽  
Synthetic Drugs ◽  
Extracellular Traps

Neutrophils are crucial elements of innate immune system, which assure host defense via a range of effector functions, such as phagocytosis, degranulation, and NET formation. The latest literature clearly indicates that modulation of effector functions of neutrophils may affect the treatment efficacy. Pharmacological modulation may affect molecular mechanisms activating or suppressing phagocytosis, degranulation or NET formation. In this review, we describe the role of neutrophils in physiology and in the course of bacterial and viral infections, illustrating the versatility and plasticity of those cells. This review also focus on the action of plant extracts, plant-derived compounds and synthetic drugs on effector functions of neutrophils. These recent advances in the knowledge can help to devise novel therapeutic approaches via pharmacological modulation of the described processes.

scholarly journals Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3321
Author(s):  
Adriana Coricello ◽  
Francesco Mesiti ◽  
Antonio Lupia ◽  
Annalisa Maruca ◽  
Stefano Alcaro
Keyword(s):  
Autoimmune Diseases ◽  
Complex Networks ◽  
Potential Application ◽  
Recent Progress ◽  
Scale Up ◽  
Drug Repurposing ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Jak Inhibitors ◽  
Stat Pathway

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

scholarly journals Modulation of Innate Immune Signaling Pathways by Herpesviruses

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 572 ◽  
Author(s):  
Qizhi Liu ◽  
Youliang Rao ◽  
Mao Tian ◽  
Shu Zhang ◽  
Pinghui Feng
Keyword(s):  
Signaling Pathways ◽  
Innate Immune ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Research Gaps ◽  
Immune Signaling ◽  
Interferon Stimulated Genes ◽  
Multiple Strategies ◽  
Innate Immune Signaling ◽  
Stat Pathway

Herpesviruses can be detected by pattern recognition receptors (PRRs), which then activate downstream adaptors, kinases and transcription factors (TFs) to induce the expression of interferons (IFNs) and inflammatory cytokines. IFNs further activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, inducing the expression of interferon-stimulated genes (ISGs). These signaling events constitute host innate immunity to defeat herpesvirus infection and replication. A hallmark of all herpesviruses is their ability to establish persistent infection in the presence of active immune response. To achieve this, herpesviruses have evolved multiple strategies to suppress or exploit host innate immune signaling pathways to facilitate their infection. This review summarizes the key host innate immune components and their regulation by herpesviruses during infection. Also we highlight unanswered questions and research gaps for future perspectives.

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 The Potential of JAK/STAT Pathway Inhibition as a New Treatment Strategy to Control Cytokine Release Syndrome in COVID-19

2020 ◽  
Author(s):  
Mohammad Seyedhamzeh ◽  
Hazha Omar Othman ◽  
Ali aghajani Sharivar ◽  
Fatemeh Aliabadi ◽  
Mehdi Shafiee Ardestani ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Viral Infections ◽  
Leukocyte Adhesion ◽  
Janus Kinase ◽  
Reaction Functions ◽  
Clinical Benefits ◽  
New Treatment ◽  
Pathway Inhibition ◽  
Insight Into ◽  
Stat Pathway

COVID-19, a pandemic affecting virus, which is caused by the current SARS-CoV2 coronavirus. The present research is performed on anti virus and immune-modulating therapies. Cytokine storms are the toxic drivers and mortality caused by various human viral infections. In addition, the intensity was linked to an elevated risk of acute respiratory failure, myocardial injury, and mortality in SARS-CoV-2-infected patients. The Janus kinase (JAK) therapeutic inhibitor class showed significant clinical benefits in anti-inflammatory and anti-viral effects. Among them, filgotinib has been approved as an active JAK inhibitor by decreasing biomarkers with main immune reaction functions and markers supporting matrix-degradation, angiogenesis, leukocyte adhesion, and recruitment in both research trials. In this study, we tried to get an insight into the choice of this drug in controlling the jack, to treat Covid 19 using drug design methods will be discussed.<br><b></b>

scholarly journals The Potential of JAK/STAT Pathway Inhibition as a New Treatment Strategy to Control Cytokine Release Syndrome in COVID-19

2020 ◽  
Author(s):  
Mohammad Seyedhamzeh ◽  
Hazha Omar Othman ◽  
Ali aghajani Sharivar ◽  
Fatemeh Aliabadi ◽  
Mehdi Shafiee Ardestani ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Viral Infections ◽  
Leukocyte Adhesion ◽  
Janus Kinase ◽  
Reaction Functions ◽  
Clinical Benefits ◽  
New Treatment ◽  
Pathway Inhibition ◽  
Insight Into ◽  
Stat Pathway

COVID-19, a pandemic affecting virus, which is caused by the current SARS-CoV2 coronavirus. The present research is performed on anti virus and immune-modulating therapies. Cytokine storms are the toxic drivers and mortality caused by various human viral infections. In addition, the intensity was linked to an elevated risk of acute respiratory failure, myocardial injury, and mortality in SARS-CoV-2-infected patients. The Janus kinase (JAK) therapeutic inhibitor class showed significant clinical benefits in anti-inflammatory and anti-viral effects. Among them, filgotinib has been approved as an active JAK inhibitor by decreasing biomarkers with main immune reaction functions and markers supporting matrix-degradation, angiogenesis, leukocyte adhesion, and recruitment in both research trials. In this study, we tried to get an insight into the choice of this drug in controlling the jack, to treat Covid 19 using drug design methods will be discussed.<br><b></b>

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