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The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 35043

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Dr. Ralf Kircheis

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Guest Editor

Syntacoll GmbH, Saal a.d.Donau, Bayern, Germany
Interests: toll-like receptors; NF-kappaB; COVID-19; cytokines; gene therapy; immune therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Oliver Planz

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Institute of Cell Biology and Immunology, Eberhard Karls University, 72076 Tuebingen, Germany
Interests: immunology of viral infections; host cell targeted antivirals; virus cell interaction
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Toll-like receptors (TLRs) represent a powerful system for the recognition and elimination of pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and other pathogens as well as damage-associated molecular patterns (DAMPs) released from dying or lytic cells. TLRs are mainly expressed on immune cells but can also be present on some tissue-resident cell populations. Typical PAMPs are cell wall components of bacterial and viral pathogens, conserved proteins, or pathogenic nucleic acids, including viral RNA and DNA.

Activation of TLRs leads to the production of proinflammatory cytokines and type I interferons, which are critical for induction of the host immune response against bacterial, fungal, and viral infections and malaria. However, dysregulation and overstimulation can be detrimental, leading to hyperinflammation, sepsis, and loss of tissue integrity. TLRs are involved in the pathogenesis of acute viral infections, including in the case of COVID-19. Altogether, the activation of TLRs plays a deciding role in both the induction of immunity and the pathophysiological effects associated with excessive activation, indicating TLRs as promising targets for pharmacological intervention and treatment.

Topics of interest include, but are not limited to:

Activation of TLRs and their downstream signaling pathways and correlation with the immunology and pathophysiology of bacterial and viral infectious diseases.
Translational research, pharmacological and medical interventions with TLR activation and signaling, and their use as therapeutic targets for bacterial and viral infectious diseases, including COVID-19.
Clinical or model studies, though only in conjunction with biomolecular experiments.

Dr. Ralf Kircheis
Prof. Dr. Oliver Planz
Guest Editors

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Keywords

toll-like receptors (TLRs)
pathogen-associated molecular patterns (PAMPs)
sepsis
bacterial infections
viral infections
Myd88
TRIF
NF-kappaB
COVID-19
coagulopathies

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The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation: Third Edition in International Journal of Molecular Sciences (4 articles)

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Editorial

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13 pages, 3463 KiB

Open AccessEditorial

Special Issue “The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0”

by Ralf Kircheis and Oliver Planz

Int. J. Mol. Sci. 2024, 25(17), 9709; https://doi.org/10.3390/ijms25179709 - 7 Sep 2024

Cited by 2 | Viewed by 1889

Abstract

Toll-like receptors (TLRs) are key players in the innate immune system, in host’ first-line defense against pathogens [...] Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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19 pages, 3210 KiB

Open AccessArticle

The Impact of Extracellular Histones and Absence of Toll-like Receptors on Cardiac Functional and Electrical Disturbances in Mouse Hearts

by Randall Loaiza, Fatemeh Fattahi, Miriam Kalbitz, Jamison J. Grailer, Mark W. Russell, Jose Jalife, Hector H. Valdivia, Firas S. Zetoune and Peter A. Ward

Int. J. Mol. Sci. 2024, 25(16), 8653; https://doi.org/10.3390/ijms25168653 - 8 Aug 2024

Cited by 1 | Viewed by 1015

Abstract

In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone–TLR interactions and their mechanisms. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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10 pages, 2659 KiB

Open AccessArticle

Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis

by Magdalena Dubik, Joanna Marczynska-Grzelak, Michael Zaucha Sørensen, Ruthe Storgaard Dieu, Dominika Rusin, Eydís Sigurdardóttir Schiöth, Bita Ramazani, Rouhin Belal, Bhavya Ojha, Jonathan Krieger, Dina S. Arengoth, Agnieszka Wlodarczyk, Trevor Owens and Reza Khorooshi

Int. J. Mol. Sci. 2024, 25(13), 7462; https://doi.org/10.3390/ijms25137462 - 7 Jul 2024

Cited by 1 | Viewed by 1479

Abstract

Regulation of neuroinflammation is critical for maintaining central nervous system (CNS) homeostasis and holds therapeutic promise in autoimmune diseases such as multiple sclerosis (MS). Previous studies have highlighted the significance of selective innate signaling in triggering anti-inflammatory mechanisms, which play a protective role in an MS-like disease, experimental autoimmune encephalomyelitis (EAE). However, the individual intra-CNS administration of specific innate receptor ligands or agonists, such as for toll-like receptor 7 (TLR7) and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2), failed to elicit the desired anti-inflammatory response in EAE. In this study, we investigated the potential synergistic effect of targeting both TLR7 and NOD2 simultaneously to prevent EAE progression. Our findings demonstrate that simultaneous intrathecal administration of NOD2- and TLR7-agonists led to synergistic induction of Type I IFN (IFN I) and effectively suppressed EAE in an IFN I-dependent manner. Suppression of EAE was correlated with a significant decrease in the infiltration of monocytes, granulocytes, and natural killer cells, reduced demyelination, and downregulation of IL-1β, CCL2, and IFNγ gene expression in the spinal cord. These results underscore the therapeutic promise of concurrently targeting the TLR7 and NOD2 pathways in alleviating neuroinflammation associated with MS, paving the way for novel and more efficacious treatment strategies. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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23 pages, 7609 KiB

Open AccessArticle

In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants

by Ralf Kircheis

Int. J. Mol. Sci. 2024, 25(10), 5451; https://doi.org/10.3390/ijms25105451 - 17 May 2024

Cited by 5 | Viewed by 1320

Abstract

The SARS-CoV-2 Omicron variants have replaced all earlier variants, due to increased infectivity and effective evasion from infection- and vaccination-induced neutralizing antibodies. Compared to earlier variants of concern (VoCs), the Omicron variants show high TMPRSS2-independent replication in the upper airway organs, but lower replication in the lungs and lower mortality rates. The shift in cellular tropism and towards lower pathogenicity of Omicron was hypothesized to correlate with a lower toll-like receptor (TLR) activation, although the underlying molecular mechanisms remained undefined. In silico analyses presented here indicate that the Omicron spike protein has a lower potency to induce dimerization of TLR4/MD-2 compared to wild type virus despite a comparable binding activity to TLR4. A model illustrating the molecular consequences of the different potencies of the Omicron spike protein vs. wild-type spike protein for TLR4 activation is presented. Further analyses indicate a clear tendency for decreasing TLR4 dimerization potential during SARS-CoV-2 evolution via Alpha to Gamma to Delta to Omicron variants. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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16 pages, 6614 KiB

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Regulation of Cathelicidin Antimicrobial Peptide (CAMP) Gene Expression by TNFα and cfDNA in Adipocytes

by Alexandra Höpfinger, Andreas Schmid, Leonie Schweitzer, Marissa Patz, Anja Weber, Andreas Schäffler and Thomas Karrasch

Int. J. Mol. Sci. 2023, 24(21), 15820; https://doi.org/10.3390/ijms242115820 - 31 Oct 2023

Cited by 3 | Viewed by 2717

Abstract

Understanding the complex interactions between metabolism and the immune system (“metaflammation”) is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP, therefore, might play a role as an adipokine in metaflammation and adipose inflammation. TNFα, cell-free nucleic acids (cfDNA), and toll-like receptor (TLR) 9 are components of the innate immune system and are functionally active in adipose tissue. The aim of the present study was to investigate the impact of TNFα and cfDNA on CAMP expression in adipocytes. Since cfDNA acts as a physiological TLR9 agonist, we additionally investigated TLR9-mediated CAMP regulation in adipocytes and adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. Adipocyte inflammation was induced in vitro by TNFα and cfDNA stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. In primary adipocytes of wildtype and TLR9 KO mice, CAMP gene expression was quantified by real-time PCR. CAMP gene expression was considerably increased in 3T3-L1 and SGBS adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was effectively antagonized by inhibition of PI3K signaling. Cell-free nucleic acids (cfDNA) significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intra-abdominal/visceral adipose tissues. Male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP gene expression levels in primary adipocytes did not significantly differ between wildtype and TLR9 KO mice. These findings suggest a regulatory role of inflammatory mediators, such as TNFα and cfDNA, in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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36 pages, 4537 KiB

Open AccessArticle

n-3 Polyunsaturated Fatty Acids Modulate LPS-Induced ARDS and the Lung–Brain Axis of Communication in Wild-Type versus Fat-1 Mice Genetically Modified for Leukotriene B4 Receptor 1 or Chemerin Receptor 23 Knockout

by Jessica Hernandez, Julia Schäffer, Christiane Herden, Fabian Johannes Pflieger, Sylvia Reiche, Svenja Körber, Hiromu Kitagawa, Joelle Welter, Susanne Michels, Carsten Culmsee, Jens Bier, Natascha Sommer, Jing X. Kang, Konstantin Mayer, Matthias Hecker and Christoph Rummel

Int. J. Mol. Sci. 2023, 24(17), 13524; https://doi.org/10.3390/ijms241713524 - 31 Aug 2023

Cited by 6 | Viewed by 2249

Abstract

Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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19 pages, 7835 KiB

Open AccessArticle

The Role of Toll-like Receptor-4 in Macrophage Imbalance in Lethal COVID-19 Lung Disease, and Its Correlation with Galectin-3

by Maria Carmela Pedicillo, Ilenia Sara De Stefano, Rosanna Zamparese, Raffaele Barile, Mario Meccariello, Alessio Agostinone, Giuliana Villani, Tommaso Colangelo, Gaetano Serviddio, Tommaso Cassano, Andrea Ronchi, Renato Franco, Paola Pannone, Federica Zito Marino, Francesco Miele, Maurizio Municinò and Giuseppe Pannone

Int. J. Mol. Sci. 2023, 24(17), 13259; https://doi.org/10.3390/ijms241713259 - 26 Aug 2023

Cited by 5 | Viewed by 2102

Abstract

To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage’s sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1⁽⁺⁾ and Spike-1⁽⁻⁾ lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3⁽⁺⁾ alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163⁽⁺⁾ myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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12 pages, 968 KiB

Open AccessCommunication

MYD88 and Proinflammatory Chemokines in Aortic Atheromatosis: Exploring Novel Statin Effects

by Konstantinos S. Mylonas, Michail Peroulis, Dimitrios Schizas and Alkistis Kapelouzou

Int. J. Mol. Sci. 2023, 24(11), 9248; https://doi.org/10.3390/ijms24119248 - 25 May 2023

Cited by 7 | Viewed by 1747

Abstract

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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Review

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From Immunity to Neurogenesis: Toll-like Receptors as Versatile Regulators in the Nervous System

by Daniela Melissa Abarca-Merlin, J. Abigail Martínez-Durán, J. David Medina-Pérez, Guadalupe Rodríguez-Santos and Lourdes Alvarez-Arellano

Int. J. Mol. Sci. 2024, 25(11), 5711; https://doi.org/10.3390/ijms25115711 - 24 May 2024

Cited by 1 | Viewed by 1424

Abstract

Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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20 pages, 853 KiB

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Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications

by Yi-Hsin Chen, Kang-Hsi Wu and Han-Ping Wu

Int. J. Mol. Sci. 2024, 25(9), 5037; https://doi.org/10.3390/ijms25095037 - 5 May 2024

Cited by 10 | Viewed by 4590

Abstract

Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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18 pages, 1736 KiB

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An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes

by Katrin Colleselli, Anna Stierschneider and Christoph Wiesner

Int. J. Mol. Sci. 2023, 24(15), 12464; https://doi.org/10.3390/ijms241512464 - 5 Aug 2023

Cited by 16 | Viewed by 5110

Abstract

While a certain level of inflammation is critical for humans to survive infection and injury, a prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation of an inflammatory process. TLR2 is one of the most studied pattern recognition receptors (PRRs) and is known to form heterodimers with either TLR1, TLR4, TLR6, and TLR10, allowing it to recognize a wide range of pathogens. Although a large number of studies have been conducted over the past decades, there are still many unanswered questions regarding TLR2 mechanisms in health and disease. In this review, we provide an up-to-date overview of TLR2, including its homo- and heterodimers. Furthermore, we will discuss the pro- and anti-inflammatory properties of TLR2 and recent findings in prominent TLR2-associated infectious and neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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20 pages, 1144 KiB

Open AccessReview

Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview

by Mohammad Enamul Hoque Kayesh, Michinori Kohara and Kyoko Tsukiyama-Kohara

Int. J. Mol. Sci. 2023, 24(11), 9624; https://doi.org/10.3390/ijms24119624 - 1 Jun 2023

Cited by 7 | Viewed by 2672

Abstract

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that play important roles in the early detection of pathogen-associated molecular patterns and shaping innate and adaptive immune responses, which may influence the consequences of infection. Similarly to other viral infections, human immunodeficiency virus type 1 (HIV-1) also modulates the host TLR response; therefore, a proper understanding of the response induced by human HIV-1 or co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), due to the common mode of transmission of these viruses, is essential for understanding HIV-1 pathogenesis during mono- or co-infection with HBV or HCV, as well as for HIV-1 cure strategies. In this review, we discuss the host TLR response during HIV-1 infection and the innate immune evasion mechanisms adopted by HIV-1 for infection establishment. We also examine changes in the host TLR response during HIV-1 co-infection with HBV or HCV; however, this type of study is extremely scarce. Moreover, we discuss studies investigating TLR agonists as latency-reverting agents and immune stimulators towards new strategies for curing HIV. This understanding will help develop a new strategy for curing HIV-1 mono-infection or co-infection with HBV or HCV. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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21 pages, 1548 KiB

Open AccessReview

TLRs: Innate Immune Sentries against SARS-CoV-2 Infection

by Stefania Mantovani, Barbara Oliviero, Stefania Varchetta, Alessandra Renieri and Mario U. Mondelli

Int. J. Mol. Sci. 2023, 24(9), 8065; https://doi.org/10.3390/ijms24098065 - 29 Apr 2023

Cited by 20 | Viewed by 4859

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been responsible for a devastating pandemic since March 2020. Toll-like receptors (TLRs), crucial components in the initiation of innate immune responses to different pathogens, trigger the downstream production of pro-inflammatory cytokines, interferons, and other mediators. It has been demonstrated that they contribute to the dysregulated immune response observed in patients with severe COVID-19. TLR2, TLR3, TLR4 and TLR7 have been associated with COVID-19 severity. Here, we review the role of TLRs in the etiology and pathogenesis of COVID-19, including TLR7 and TLR3 rare variants, the L412F polymorphism in TLR3 that negatively regulates anti-SARS-CoV-2 immune responses, the TLR3-related cellular senescence, the interaction of TLR2 and TLR4 with SARS-CoV-2 proteins and implication of TLR2 in NET formation by SARS-CoV-2. The activation of TLRs contributes to viral clearance and disease resolution. However, TLRs may represent a double-edged sword which may elicit dysregulated immune signaling, leading to the production of proinflammatory mediators, resulting in severe disease. TLR-dependent excessive inflammation and TLR-dependent antiviral response may tip the balance towards the former or the latter, altering the equilibrium that drives the severity of disease. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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