Toll-like receptors (TLRs) are fundamental sensor molecules of the host innate immune system, which detect conserved molecular signatures of a wide range of microbial pathogens and initiate innate immune responses via distinct signaling pathways. Various TLRs are implicated in the early interplay of host cells with invading viruses, which regulates viral replication and/or host responses, ultimately impacting on viral pathogenesis. To survive the host innate defense mechanisms, many viruses have developed strategies to evade or counteract signaling through the TLR pathways, creating an advantageous environment for their propagation. Here we review the current knowledge of the roles TLRs play in antiviral innate immune responses, discuss examples of TLR-mediated viral recognition, and describe strategies used by viruses to antagonize the host antiviral innate immune responses.
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The results further suggested that released or secreted S protein could activate blood monocytes through recognition by toll-like receptor (TLR)2 ligand.
SARS-CoV regulates immune function-related gene expression in human monocytic cells..at 24 h after SARS-CoV infection: (1) IFN-α/β-inducible and cathepsin/proteasome genes were downregulated; (2) hypoxia/hyperoxia-related genes were upregulated; and (3) TLR/TLR-signaling, cytokine/cytokine receptor-related, chemokine/chemokine receptor-related, lysosome-related, MHC/chaperon-related, and fibrosis-related genes were differentially regulated. These results elucidate that SARS-CoV infection regulates immune-related genes in monocytes/macrophages, which may be important to the pathogenesis of SARS.
Toll-like receptors are a family of sensor proteins that enable the immune system to differentiate between "self" and "non-self." Agonists and antagonists of TLRs have been proposed to have utility as vaccine adjuvants or antiviral compounds. In the last 15 years, the emergence of highly pathogenic coronaviruses SARS-CoV and MERS-CoV has caused significant disease accompanied by high mortality rates in human populations, but no approved therapeutic treatments or vaccines currently exist. Here, we demonstrate that TLR signaling through the TRIF adaptor protein protects mice from lethal SARS-CoV disease. Our findings indicate that a balanced immune response operating through both TRIF-driven and MyD88-driven pathways likely provides the most effective host cell intrinsic antiviral defense responses to severe SARS-CoV disease, while removal of either branch of TLR signaling causes lethal SARS-CoV disease in our mouse model. These data should inform the design and use of TLR agonists and antagonists in coronavirus-specific vaccine and antiviral strategies.
Our working hypothesis is that the violent inflammatory response to SARS-CoV, linked to ARDS, in some cases to sepsis and leading in any case to high mortality, is caused by the excessive activation of Toll-like Receptor 4 (TLR4), one of the most important receptors expressed on cells of the immune system. TLR4, that normally responds to the presence of gram-negative bacteria endotoxin (mainly lipopolysaccharide, LPS), triggering the inflammatory and innate immunity response, can be also activated by endogenous molecules, called Damage-Associated Molecular Pattern molecules (DAMPs), released by the pulmonary tissue damaged by viral infection. In the case of SARS-CoV2 infection, the DAMPs released as a consequence of the acute lung injury (ALI), encompass oxidized phospholipids and, very likely, the protein HMGB1юToll-like Receptor TLR4, mainly expressed on cells of the immune system including monocytes, macrophages and dendritic cells, is the PRR that senses gram-negative bacteria endotoxin (LPS). LPS is a highly potent inflammatory stimulus, and LPS/TLR4 signalling has been strongly implicated in Gram-negative septic shock, including acute respiratory distress syndrome caused by endothelial leak. TLR4 has also been shown to be a sensor for endogenous DAMPs, included HMGB1. Stimulation of TLR4 by PAMPs or DAMPs results in the activation of two different intracellular signal pathways, the myeloid differentiation primary response 88 (MyD88), and/or toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF), ultimately resulting in the expression and secretion of pro-inflammatory mediators. Influenza-infected MyD88-/- and MyD88/TRIF doubly deficient mice show a marked reduction of pulmonary cytokine production when compared with WT mice, indicating the important role of these TLR signalling pathways in disease. Chemical or microbial insults to lung tissues, trigger the production of DAMPs such as oxidized phospholipids and HMGB1 protein, starting a common TLR4-, TRIF-, and IL-6-dependent pathway in macrophages that leads to acute lung injury (ALI).
We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses. ...and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19. Finally, this study is expected to improve our understanding on the immunobiology of SARS-CoV-2 and could be useful in adopting spike protein, ACE2, or TLR-guided intervention strategy against COVID-19 shortly.
COVID-19 patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis.
We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls. Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker.These data support a link between TLR4 signaling and pathological inflammation during COVID-19
The chronic inflammatory process found in these cardiometabolic comorbidities is marked by the overexpression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α), which are products of the Toll-Like receptors 4 (TLR4) pathway.
We hypothesize that this happens because the SARS-CoV-2 spike protein interacts strongly with TLR4, causing an intensely exacerbated immune response in the host's lungs, culminating with the cytokine storm, accumulating secretions and hindering blood oxygenation
Here, we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19
To elucidate the inflammatory mechanisms involved in COVID-19, we examined the effects of SARS-CoV-2 spike protein S1 subunit (hereafter S1) on the pro-inflammatory responses in murine and human macrophages.Murine peritoneal exudate macrophages produced pro-inflammatory mediators in response to S1 exposure. Exposure to S1 also activated nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) signaling pathways. Similar results were obtained in experiments using TLR4 siRNA-transfected murine RAW264.7 macrophages.SARS-CoV-2 spike protein S1 subunit activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. Therefore, TLR4 signaling in macrophages may be a potential target for regulating excessive inflammation in COVID-19 patients.