TLR4 as a therapeutic target for respiratory and neurological complications of SARS-CoV-2

ABSTRACT

Introduction: The COVID-19 pandemic remains aglobal challenge. While there are mRNA agents on the horizon as apotential prevention, adefinitive drug therapy is an unmet medical need. The hyperinflammatory response, known as the ‘cytokine storm’, is chiefly responsible for complications and deaths. The binding of spike-glycoprotein of SARS-CoV-2 to TLR4 receptors has been documented in several studies and has been found to play arole in hyperinflammation; hence, there is an interest in TLR4 as apotential drug target.

Areas covered: This review discusses the neurological and respiratory complications of SARS-CoV-2 infection and progresses to examine the role of the ‘cytokine storm’ and the involvement of TLR4 receptors in these complications. The possibility of using TLR4 modulators to curb the complications are considered and finally, ashort perspective on future potential drug treatments is offered. Various databases were searched including Pub-Med, Google Scholar, and Medline. The search mainly included research articles, meta-analysis, retrospective studies, reports, and systematic reviews.

Expert opinion: TLR4 modulators are being investigated in clinical trials for COVID-19. Challenges in terms of structural diversity of the agents, their natural origin, and efficacy demand extensive research.

KEYWORDS:

• Sars-cov-2
• covid-19
• coronavirus
• acute respiratory distress syndrome
• toll-like receptors
• tlr-4
• cytokine storm
• neurological complications

Article highlights

• Vaccines potentially offer prevention of SARS-COV2, but not an effective curative treatment; hence finding new drug targets is a necessary starting block.

• The chief culprit behind SARS-COV2 complications is the hyperinflammatory cascade, known as the ‘cytokine storm’.

• TLR4 receptors are involved in immune response and further lead to signaling of inflammatory molecules.

• Interaction of spike glycoprotein with TLR4 and elevation of genes associated with TLR4 signaling in COVID-19 point to the possible involvement of these receptors and their inflammatory cascade.

• Modulating TLR4 activity appears to offer promise in the search for new drugs for SARS-COV2

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose