Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections
Clinton Njinju Asaba, Cyril Jabea Ekabe, Humblenoble Stembridge Ayuk, Bella Nyemkuna Gwanyama, Razieh Bitazar, Terence Ndonyi Bukong
Journal of Inflammation Research, doi:10.2147/jir.s474707
The late 2019 emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, caused profound and unprecedented disruption to the global socio-economic structure, negatively affecting millions of lives worldwide. A typical hallmark of severe COVID-19 is hyper inflammation due to aberrant cytokine release (cytokine storm) by innate immune cells. Recent studies have revealed that SARS-CoV-2, through its spike (S) protein, can activate the body's innate immune cells via Toll-Like Receptors (TLRs), particularly TLR4. In silico studies have demonstrated that the S protein binds with high affinity to TLR4, triggering downstream signaling processes that result in pro-inflammatory cytokine release. Compared to other TLRs, such as TLR2, TLR4 plays a more significant role in initiating and sustaining the inflammatory response associated with severe COVID-19. Furthermore, interactions between the virus and target cells can enhance the cellular expression of TLR4, making cells more susceptible to viral interactions and subsequent inflammation. This increased expression of TLR4 upon viral entry creates a feedback loop, where heightened TLR4 levels lead to amplified inflammatory responses, contributing to the severity of the disease. Additionally, TLR4's potent activation of inflammatory pathways sets it apart from other TLRs, underscoring its pivotal role in the pathogenesis of COVID-19. In this review, we thoroughly explore the multitude of regulatory signaling pathways that SARS-CoV-2 employs to incite inflammation. We specifically focus on the critical impact of TLR4 activation compared to other TLRs, highlighting how TLR4's interactions with the viral S protein can exacerbate the severity of COVID-19. By delving into the mechanisms of TLR4mediated inflammation, we aim to shed light on potential therapeutic targets that could mitigate the inflammatory damage caused by severe COVID-19. Understanding the unique role of TLR4 in the context of SARS-CoV-2 infection could pave the way for novel treatment strategies that specifically inhibit this receptor's activity, thereby reducing the overall disease burden and improving patient outcomes.
Abbreviations ACE2, Angiotensin-converting enzyme 2; AP-1, activator protein-1; ARDS, acute respiratory distress syndrome; ATI, alveolar type I pneumocytes; ATII, alveolar type II pneumocytes; AT1-R, Angiotensin II Type 1 Receptor; AT2-R, Angiotensin II Type 2 Receptor; DAMPs, danger associated molecular patterns; FAK, focal adhesion kinase; IRF3, interferon regulatory factor-3; LBP, LPS binding protein; MD2, myeloid differentiation factor 2; MyD88, myeloid differentiation primary response 88; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, Nuclear factor-kB; NSAIDs, Non-steroidal anti-inflammatory drugs; PAMPs, pathogen associated molecular patterns; PLC, phospholipase C; PSGL-1, P-selectin glycoprotein ligand 1; RAS, renin-angiotensin system; RBD, receptor-binding domain; sGP, secreted glycoprotein; TF, tissue factor; TIR, toll-IL1 receptor; TLR, Toll-like receptor; TMPRSS2, transmembrane serine protease 2; TRIF, toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β.
Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
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