Potential value of pharmacological agents acting on toll-like receptor (TLR) 7 and/or TLR8 in COVID-19

Abstract

The COVID-19 pandemic is an ongoing global pandemic of coronavirus disease 2019 as an atypical type of viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many potential pharmacotherapies are currently being investigated against this disease. This article points to and justifies, the importance of investigating the potential therapeutic value of pharmacological agents acting on Toll-like Receptor (TLR) 7 and/or TLR8 as double-edged swords combating COVID-19. Induction of TLR7 and/or TLR8 may be investigated as a strategy to stimulate immunity and may be added to anti-COVID19 vaccines to cope with their current viral escape challenge. TLR7 stimulation may not only help viral clearance through Th1 antiviral responses but may also provide beneficial broncho- and vaso-dilatory, as well as, anti-inflammatory effects. Pharmacological compounds acting as TLR7 and/or TLR8 agonists may be of value if used by frontline healthcare workers with comorbidities who demonstrate mild symptoms of the disease. On the other hand, TLR7 and/or TLR8 antagonists may be used in combination with immune-modulatory/anti-inflammatory drugs in severe cases of the disease, with potential synergistic effects that could also help in reducing the doses of such therapies, and consequently their adverse effects.

Keywords: Agonists; Antagonists; COVID-19; TLR7; TLR8; Vaccines.

Fig. 1

TLR7/8 agonists as immuno-stimulants against SARS-CoV-2-induced mild-to-moderate COVID-19. TLR7/8, situated in endosomes, play a key role in the recognition of SARS-CoV-2 causing COVID-19. Through activation of the innate immune system, TLR7/8 are involved in a plethora of intracellular signaling cascades which culminate in the gene expression of pro-inflammatory cytokines and chemokines. In addition, TLR7/8 are coupled to the adaptor protein MyD88 which activates downstream NF-κB driven genes. TLR7/8 agonists have been reported active against several ssRNA viruses including SARS-CoV-2, through enhancing both innate and adaptive immunity. They may not only help early viral clearance through Th1 antiviral responses but may also provide broncho-dilating and anti-inflammatory effects via production of NO. Moreover, TLR7/8 agonists can be used as vaccine adjuvants able to induce humoral and cellular immunity coping with the major challenge of current anti-COVID19 vaccines which is viral escape. The underlying adjuvant immunostimulatory mechanism is by stimulating the innate immunity via production of cytokines/chemokines and type I interferons, followed by immediate development of adaptive immune responses so that host protection against the virus is strengthened and lasts longer. COVID-19, coronavirus disease 2019; MYD88, myeloid differentiation primary response 88; NF-kB, nuclear factor k-light-chain-enhancer; NO, nitric oxide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ssRNA, single strand RNA; Th1, T-helper 1 ​cells; TLR7/8, toll-like receptors 7 and/or 8.

Fig. 2

TLR7/8 antagonists as immuno-suppressants against SARS-CoV-2-induced severe COVID-19. TLR7/8 antagonists were suggested to play key roles in suppressing the pathogenesis of the cytokine release syndrome in severe COVID-19 patients. TLR7/8 antagonists modulate immune responses and down-regulate cytokine production and may reduce life-threatening complications of COVID-19, including severe lymphopenia and SARS. They act against excessive levels of pro-inflammatory cytokines/chemokines and type I interferons including TNF–α, IL-1, IFN-ɣ, IL-6, & IL-12. The combined administration of TLR7/8 antagonists with immunomodulating, and anti-inflammatory pharmacotherapies classically used to target the cytokine storm, may have a synergistic effect that could help in reducing the dose of such therapies and consequently their adverse effects in more advanced late stages of the disease till returning with host immunity to recovery. COVID-19, coronavirus disease 2019; IFN-ɣ, inteferon gamma; TNF–α, tumour necrosis factor alpha; IL, interleukin; MYD88, myeloid differentiation primary response 88; NF-kB, nuclear factor k-light-chain-enhancer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TLR7/8, toll-like receptors 7 and/or 8.