Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections

Abstract

Clinton Njinju Asaba,1 Cyril Jabea Ekabe,2 Humblenoble Stembridge Ayuk,3 Bella Nyemkuna Gwanyama,4 Razieh Bitazar,1 Terence Ndonyi Bukong1 1Armand-Frappier Sante Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, Québec, Canada; 2Department of Translational Biomedical Sciences, University of Rochester, Rochester, NY, USA; 3Department of Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, 04318, Germany; 4Department of Microbiology & Immunology, McGill University, Montreal, Québec, CanadaCorrespondence: Terence Ndonyi Bukong, Email [email protected]: 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 TLR4-mediated 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.Keywords: SARS-CoV-2, cytokine storm, toll-like receptor 4, hyperinflammation, ACE2 receptors, innate immunity

Keywords

• sars-cov-2
• cytokine storm
• toll-like receptor 4
• hyperinflammation
• ace2 receptors
• innate immunity