Anti-Viral Pattern Recognition Receptors as Therapeutic Targets.
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ABSTRACT:
SUBMITTER: Hennessy C
PROVIDER: S-EPMC8466445 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The pattern recognition receptors of the innate immune system are part of the first line of defence against pathogens. However, they also have the ability to respond to danger signals that are frequently elevated during tissue damage and at sites of inflammation. Inadvertent activation of pattern recognition receptors has been proposed to contribute to the pathogenesis of many conditions including inflammatory rheumatic diseases. Prolonged inflammation most often results in pain and damage to tissues. In particular, the Toll-like receptors and nucleotide-binding oligomerisation domain-like receptors that form inflammasomes have been postulated as key contributors to the inflammation observed in rheumatoid arthritis, osteoarthritis, gout and systemic lupus erythematosus. As such, there is increasing interest in targeting these receptors for therapeutic treatment in the clinic. Here the role of pattern recognition receptors in the pathogenesis of these diseases is discussed, with an update on the development of interventions to modulate the activity of these potential therapeutic targets.
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Project description:Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.
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Project description:Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.
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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the important causes of mortality due to malignancy. Toll-like receptors (TLRs) are very important in liver pathophysiology in terms of their roles in the innate immune system, such as the regulation of inflammation, wound healing, stimulation of adaptive immune responses, promotion of epithelial regeneration, and carcinogenesis. In this study, we planned to examine the role of TLR1 (rs4833095, rs5743551) and nucleotide-binding oligomerization domain (NOD2) (rs2066844, rs2066845, rs2066847) polymorphisms in the development of HCC and their effects on the clinical presentation of HCC patients.MethodsOur study was designed prospectively. Cirrhotic and HCC patients who were followed up in our clinic between January 2015 and September 2018 were included in the study. Sex, age, cirrhosis etiology, Child-Pugh class, and MELD scores were recorded. TLR1 and NOD2 polymorphisms were studied by the PCR method.ResultsHCC developed in 88 (31.4%) of the 280 patients who were followed up, either during the recruitment phase of our study or during the follow-up. The mean follow-up time of our patient group was 17.04 ± 11.72 months, and the mean follow-up time of HCC patients was 12.09 ± 10.26 months. TLR1 (rs5743551) polymorphism was associated with HCC development (P = .003). TLR1 (rs5743551) and NOD2 (rs2066844) polymorphisms were associated with the development of spontaneous bacterial peritonitis (SBP) in the HCC patient group (P = .013 and P = .021, respectively).ConclusionWe think that increased bacterial translocation in cirrhotic patients may contribute to HCC development by causing chronic inflammation, especially in patients with TLR 1 (rs5743551) polymorphism.
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