Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019

Abstract

Toll-like receptors (TLRs) are key sensors that recognize the pathogen-associated molecular patterns (PAMPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate innate immune response to clear the invading virus. However, dysregulated immune responses may elicit the overproduction of proinflammatory cytokines and chemokines, resulting in the enhancement of immune-mediated pathology. Therefore, a proper understanding of the interaction between SARS-CoV-2 and TLR-induced immune responses is very important for the development of effective preventive and therapeutic strategies. In this review, we discuss the recognition of SARS-CoV-2 components by TLRs and the downstream signaling pathways that are activated, as well as the dual role of TLRs in regulating antiviral effects and excessive inflammatory responses in patients with coronavirus disease 2019 (COVID-19). In addition, this article describes recent progress in the development of TLR immunomodulators including the agonists and antagonists, as vaccine adjuvants or agents used to treat hyperinflammatory responses during SARS-CoV-2 infection.

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…TLR4 activation in platelets whether by pathogen-(viremia) or damage-associated molecular patterns induces a prothrombotic and proinflammatory state(Schattner, 2019). Activation of endosomal TLR7/8 during SARS-CoV-2 may increase the inflammatory response resulting in severe and potentially lethal immunopathological effects in COVID-19 patients as consequence of the simultaneous release of pro-inflammatory cytokines and chemokines(Dai et al, 2022) TLRs play a key role in microorganism and viral particle recognition and activation of the innate immune system and although pathogen-associated molecular pattern(PAMP) recognition by TLRs is crucial for host defense responses to pathogen infection, aberrant activation of TLR signaling by PAMPs, mutations of TLR signaling molecules, and damage-associated molecular patterns (DAMPs)-mediated TLRs signaling activation are responsible for the development of chronic inflammatory diseases(Sasai and Yamamoto, 2013;Kawasaki and Kawai, 2014;McClure and Massari, 2014;Sartorius et al, 2021;Manik and Singh, 2022) GSH and GSH enhancers could neutralize oxidation radicals generated during TLRmediated mitochondrial ROS production and directly affect SARS-CoV-2-mediated cellular and tissue damage(Aboudounya and Heads, 2021); TLR inhibitors/immunomodulators could become promising treatments for severe COVID-19(Jung and Lee, 2021;Dai et al, 2022)…”

An insight overview on COVID-19 mRNA vaccines: Advantageous, pharmacology, mechanism of action, and prospective considerations

“…The structure of TLRs as the type I transmembrane proteins) consists of a TIR domain, a transmembrane region, and a leucine-rich repeat (LRR) module. TLRs recognize pathogen-associated molecular patterns with their LRR motif and generate intracellular signals with the TIR domain [59] . TLRs are divided into two general categories based on their location.…”

“…TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the surface of the cell membrane, while TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles. These TLRs are distributed in lysosomes, endoplasmic reticulum, and endosomes [59] . Since the mRNA molecules are considered as the strong activators of TLR7/8.…”

Role of different types of RNA molecules in the severity prediction of SARS-CoV-2 patients

“…Next set of features are related to the prediction of treatment stage of the COVID-19 patients. Same analysis on those genes shows that they are closely related to the biological processes such as neutral amino acid transport [95] , regulation of cellular protein metabolic process [84] , negative regulation of cellular macromolecule biosynthetic process [93] , endosome to lysosome transport [50] , chondrocyte morphogenesis involved in endochondral bone morphogenesis, growth plate cartilage chondrocyte morphogenesis, ferrochelatase activity, chondrocyte morphogenesis, phosphatase activator activity [116] , regulation of protein kinase activity [52] , [79] , negative regulation of cellular metabolic process [11] , [8] , response to inorganic substance [111] , [22] , toll-like receptor 9 signaling pathway [1] , [25] , [49] , [70] , [90] , positive regulation of NIK/NF-kappaB signaling [54] , myeloid dendritic cell activation [6] , [85] , regulation of transcription from RNA polymerase II promoter, protein localization to cilium, positive regulation of cell morphogenesis involved in differentiation, mRNA/RNA polyadenylation [102] , [5] , protein localization to cilium, phosphatidylinositol binding, optic cup structural organization [2] , endosome to plasma membrane transport vesicle, SET domain binding, negative regulation of phosphorus metabolic process [110] , regulation of fatty acid transport/ long-chain fatty acid transport [101] , [108] , [32] , [94] , positive regulation of mRNA catabolic process [87] , positive regulation of mRNA metabolic process [54] , transcription from RNA polymerase II promoter, positive regulation of cellular biosynthetic process, negative regulation of RNA metabolic process, negative regulation of nitrogen compound metabolic process [16] , [76] and negative regulation of cellular macromolecule biosynthetic process [30] .…”