ReviewInternational journal of molecular sciences2021
Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions.
Review in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 112 citations in OpenAlex.
- Hemoadsorption in acute respiratory distress syndrome patients requiring venovenous extracorporeal membrane oxygenation: a systematic review.Respiratory research · 2024Pooled it
- Trial
- A developmentally informed narrative review of Toll-like receptors in adult and pediatric acute respiratory distress syndrome.Annals of translational medicine · 2026Review
- Exploring possible mechanisms of antiviral effect of Shufeng Jiedu Capsule on viral pneumonia: A comprehensive analysis.Chinese herbal medicines · 2026Article
- PEBL, a component-based Chinese medicine, reduces virus-induced acute lung injury by targeting FXR to decrease ACE2 levels.Journal of advanced research · 2026Article
- The SINE in CDR2 gene associated with the resistance to lung diseases in Xiang pigs.BMC genomics · 2026Article
- Inhalable songorine-integrated lipid nanomedicine for targeted ARDS therapyActa pharmaceutica Sinica. B · 2026Article
- Hexapeptide-Liposome Nanosystem for the Delivery of Endosomal pH Modulator to Treat Acute Lung Injury.Journal of functional biomaterials · 2025Article
- The Way of SARS-CoV-2 Pneumonia-An Early-Pandemic Review of the Key Manifestations and Severity.Journal of clinical medicine · 2025Review
- Aromatic Molecular Compatibility Attenuates Influenza Virus-Induced Acute Lung Injury via the Lung-Gut Axis and Lipid Droplet Modulation.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy.Signal transduction and targeted therapy · 2025Review
- NLRP3 promotes inflammatory signaling and IL-1β cleavage in acute lung injury caused by cell wall extract of Lactobacillus casei.Communications biology · 2025Article
- NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.Current issues in molecular biology · 2024Review
- Effects of aging and lifelong aerobic exercise on expression of innate immune components in skeletal muscle of women.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Article
- T-Cell Receptor Sequences Identify Combined Coxsackievirus-International journal of molecular sciences · 2024Article
- SARS-CoV-2 infection causes dopaminergic neuron senescence.Cell stem cell · 2024Article
- Platelet P2YBritish journal of pharmacology · 2024Review
- Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS).Respiratory research · 2024Review
- Identification of the feature genes involved in cytokine release syndrome in COVID-19.PloS one · 2024Article
- Role of Cellular Senescence Genes and Immune Infiltration in Sepsis and Sepsis-Induced ARDS Based on Bioinformatics Analysis.Journal of inflammation research · 2024Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Severe COVID-19 is characterized by a "cytokine storm", the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.