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
Abstract
:1. Introduction: The Problem of What Causes Cytokine Overproduction Syndromes
2. Innate Immune System Receptor Activation in Cytokine Storms
2.1. The Presence of Multiple Concurrent Infections in Cytokine Release Syndromes
2.2. Overview of Receptor Regulation of Cytokine Production
2.3. Synergistic and Antagonistic Receptor Interactions within the Innate Immune System
2.4. A Hypothesis Concerning the Mechanism Producing Cytokine Storms
2.5. Methods for Reviewing Literature Relevant for Comparing Alternative Hypotheses
2.6. Synergistic and Antagonistic Receptor Activation Networks in Severe COVID-19, ALI/ARDS and Sepsis
2.7. Varied Receptor Activation by PAMP Produced by Different Pathogens
2.8. Innate Receptor Activation by Bacterial and Fungal Infections Associated with Coronavirus, Influenza and Other ALI/ARDS Syndromes
2.9. Do Combinations of Viruses and Bacteria Explain Innate Receptor Activation Patterns in Severe COVID-19 and ALI/ARDS?
2.10. Role of DAMPs in Driving COVID-19 and Other Cytokine Release Syndromes
3. Discussion
3.1. Summary of the Synergistic Activation of TLR and NLR in Cytokine Storm Syndromes
3.2. The Role of Pathogen Synergisms in COVID-19
3.3. Implications of Innate Receptor Activation Profiles for Tretment of COVID-19 and Other Cytokine Release Syndromes
3.4. Directions for Future Research
3.5. Limitations and Sources of Bias in This Study
4. Conclusions
Funding
Conflicts of Interest
References
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Receptors | TLR1 | TLR2 | TLR3 | TLR4 | TLR5 | TLR6 | TLR7 | TLR8 | TLR9 | TLR10 | NOD1 | NOD2 | NL-RP3 | RIG1 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Activated by: | Lipo-peptides | Gram-PGN, LTA & HSP, HMGB1 | ds-RNA, polyI:C, DAMP | Gram+ LPS & HSP, HMGB1 | Flagellin | LTA, lipopeps | ss-RNA | ss- RNA & pyogenic Bacteria | CpG DNA & mtDNA | Retroviral RNA | Meso-DAP | MDP | ? | Viral RNA |
COVID-19 SEVERE | - | ^ | +/- | ^ | - | - | ^ | - | +/- | - | - | - | ^ | - |
INFLUENZA-ASSOCIATED ALI/ARDS | v | ^ | ^ | ^ | - | ^ | +/- | ^ | ^ | v | ||||
SEPSIS/ALI (murine) | ^ | +/- | ^ | - | ^ | ^ | - | - | ^ | |||||
SEPSIS human patients | - | +/- | - | ^ | +/- | - | +/- | - | -/v | - | - | - | ^ | |
Polymicrobial SEPSIS murine model | - | ^ | - | ^ | - | - | ^ | - | - | - | - | ^ | ||
SEPSIS CONCENSUS | - | ^ | - | ^ | - | - | ^ | - | - | - | - | ^ |
Receptor: | TLR 1 | TLR 2 | TLR 3 | TLR 4 | TLR 5 | TLR 6 | TLR 7 | TLR 8 | TLR 9 | TLR 10 | NOD 1 | NOD 2 | NL-RP 3 | RIG 1 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Activated by: | Lipopeptides | Gram- PGN, LTA & HSP, HMGB1 | ds-RNA, polyI:C, DAMP | Gram+ LPS & HSP, HMGB1 | Flagellin | LTA, lipopeps | ss-RNA | ss- RNA & pyogenic Bacteria | CpG DNA & mtDNA | Retroviral RNA | Meso-DAP | MDP | ? | Viral RNA |
CoV 229E | - | - | - | ^ | - | v | ||||||||
SARS-CoV-1 | - | +/- | ^ | - | - | - | ^ | ^ | v | - | ^ | v | ||
MERS | ^ | v | ^ | +/- | ^ | v | ||||||||
SARS-CoV-2 | +/- | ^ | ^ | ^ | ^ | v | ||||||||
Coronavirus CONCENSUS | ^ | ^ | ^ | v | ||||||||||
Influenza A viruses | - | v | ^ | v | - | - | ^ | ^ | ^ | - | ^ | ^ | ^ | |
Rhinoviruses | ^ | ^ | - | +/- | ||||||||||
Respiratory syncytial virus | - | - | ^ | +/- | - | ^ | ^ | +/- | ^ | ^ | ^ | |||
Adenovirus | ^ | ^ | ^ | ^ | ^ | |||||||||
Coxsackie-viruses | ^ | ^ | ^ | ^ | ^ | ^ | ^ | |||||||
RESP VIRUS CONCENSUS | - | - | ^ | - | - | - | ^ | ^ | ^ | ^ | ^ | ^ |
TLR 1 | TLR 2 | TLR 3 | TLR 4 | TLR 5 | TLR 6 | TLR 7 | TLR 8 | TLR 9 | TLR 10 | NOD 1 | NOD 2 | NL-RP3 | RIG 1 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Lipopeptides | Gram- PGN, LTA & HSP, HMGB1 | ds-RNA, polyI:C, DAMP | Gram+ LPS & HSP, HMGB1 | Flagellin | LTA, lipopeps | ss-RNA | ss- RNA & pyogenic Bacteria | CpG DNA & mtDNA | Retroviral RNA | Meso-DAP | MDP | ? | Viral RNA | |
GRAM POS | ||||||||||||||
Group A Streptococci | ^ | ^ | - | ^ | - | - | - | ^ | - | - | ^ | ^ | ||
Group B Streptococci | - | ^ | ^ | ^ | - | - | ^ | |||||||
Staphylococcus aureus | ^ | ^ | ^ | ^ | - | ^ | ^ | |||||||
GRAM AMBI | ||||||||||||||
Mycobacterium tuberculosis | ^ | ^ | +/- | ^ | ^ | ^ | ^ | |||||||
GRAM NEG | ||||||||||||||
Klebsiella pneumoniae | ^ | ^ | ^ | ^ | ^ | |||||||||
Haemophilus influenzae | ^ | +/- | - | ^ | ^ | ^ | ||||||||
Legionella pneumophila | ^ | ^ | ^ | - | - | ^ | ||||||||
Chlamydia pneumoniae | ^ | ^ | ^ | ^ | ^ | |||||||||
Neisseria meningitidis | ^ | ^ | ^ | ^ | ^ | ^ | ||||||||
Pseudomonas aeruginosa | ^ | ^ | ^ | ^ | ^ | ^ | ||||||||
NO GRAM | ||||||||||||||
Mycoplasma pneumoniae | ^ | ^ | ^ | ^ | - | - | ^ | |||||||
BACTERIA CONCENSUS | ^ | ^ | ^ | ^ | +/- | ^ | ^ |
TLR 1 | TLR 2 | TLR 3 | TLR 4 | TLR 5 | TLR 6 | TLR 7 | TLR 8 | TLR 9 | TLR 10 | NOD 1 | NOD 2 | NL-RP 3 | RIG 1 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Lipopeptides | Gram- PGN, LTA & HSP, HMGB1 | ds-RNA, polyI:C, DAMP | Gram+ LPS & HSP, HMGB1 | Flagellin | LTA, lipopeps | ss-RNA | ss-RNA & pyogenic Bacteria | CpG DNA & mtDNA | Retroviral RNA | Meso-DAP | MDP | ? | Viral RNA | |
Aspergillus spp. | ^ | ^ | ^ | ^ | ^ | ^ | ^ | |||||||
Candida spp. | ^ | ^ | ^ | ^ | ^ | - | ^ | |||||||
Cryptococcus spp. | ^ | ^ | ^ | ^ | ^ | |||||||||
FUNGI CONSENSUS | ^ | ^ | ^ | ^ | ^ |
TLR 1 | TLR 2 | TLR 3 | TLR 4 | TLR 5 | TLR 6 | TLR 7 | TLR 8 | TLR 9 | TLR 10 | NOD 1 | NOD 2 | NLRP 3 | RIG 1 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
@@ | Lipo-peptides | Gram- PGN, LTA & HSP, HMGB1 | ds-RNA, polyI:C, DAMP | Gram+ LPS & HSP, HMGB1 | Flagellin | LTA, lipopeps | ss-RNA | ss- RNA & pyogenic Bacteria | CpG DNA & mtDNA | Retroviral RNA | Meso-DAP | MDP | ? | Viral RNA |
Coronavirus CONSENSUS | ^ | ^ | ^ | v | ||||||||||
RESP VIRUS CONCENSUS | - | - | ^ | - | - | - | ^ | ^ | ^ | ^ | ^ | ^ | ||
BACTERIA CONSENSUS | ^ | ^ | ^ | G+ G- | ^ | ^ | ||||||||
FUNGI CONSENSUS | ^ | ^ | ^ | ^ | ^ | |||||||||
COVID-19 SEVERE CONSENSUS | - | ^ | +/- | ^ | - | - | ^ | - | +/- | - | - | - | ^ | - |
INFLUENZA-ASSOCIATED ALI/ARDS | v | ^ | ^ | ^ | - | ^ | +/- | ^ | ^ | v | ||||
SEPSIS human patients | - | +/- | - | ^ | +/- | - | +/- | - | -/v | - | - | - | ^ |
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Root-Bernstein, R. 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. Int. J. Mol. Sci. 2021, 22, 2108. https://doi.org/10.3390/ijms22042108
Root-Bernstein R. 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. International Journal of Molecular Sciences. 2021; 22(4):2108. https://doi.org/10.3390/ijms22042108
Chicago/Turabian StyleRoot-Bernstein, Robert. 2021. "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" International Journal of Molecular Sciences 22, no. 4: 2108. https://doi.org/10.3390/ijms22042108