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

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.

Possible Link between SARS-CoV-2 Infection and Parkinson’s Disease: The Role of Toll-Like Receptor 4

“…The activation of TLR7/8 has been found to evoke a strong pro-inflammatory response during acute lung injury [120]. Furthermore, the binding of SARS-CoV-2 PAMPs to the extracellular domain of human TLR1, TLR4, and TLR6 seems to be crucial for COVID-19 immunopathogenesis [121,122].…”

“…Although the host genetic background powerfully influences the requirement for TLR4-mediated signals during SARS-CoV-2 infection, TLR4 activation seems to represent one of the critical steps for host-virus general interaction [122]. It has been demonstrated that TLR4 deficiency can induce resistance to acute manifestations that accompany the viral attack, suggesting an important role of TLR4 signaling in the profuse pro-inflammatory cytokine storm [123].…”

The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza

“…Whereas endosomal TLR3 detects double-stranded RNA (dsRNA), TLR7 and TLR8 sense single-stranded RNA (ssRNA); RIG-I specifically recognizes 5'-triphosphate RNA; and NLRs may directly recognize viral products, leading to the formation of inflammasomes ( Biondo et al, 2019 ). RIG-I and NLRs have been comprehensively reviewed elsewhere ( Root-Bernstein, 2021 ) and will not be covered in more detail here.…”

The pivotal roles of the host immune response in the fine-tuning the infection and the development of the vaccines for SARS-CoV-2

“…The TLR-4 expresses at the surface of airway epithelial cells, macrophages may recognize the (s) protein, and once the virus releases its genomic RAN material into the cytoplasm during replication. 119 The endoplasmic RNA sensors such as TLR-3, TLR-7, and TLR-8 can further recognize it; 120 this may result in the induction of both the cytokines and the chemokines. Moreover, the infected host cells produce a wide range of pro-inflammatory cytokines and chemokines that also able to recruit several inflammatory cells at the site of infection.…”