Induction of Innate Immune Response by TLR3 Agonist Protects Mice against SARS-CoV-2 Infection

Tamir, Hadas; Melamed, Sharon; Erez, Noam; Politi, Boaz; Yahalom-Ronen, Yfat; Achdout, Hagit; Lazar, Shlomi; Gutman, Hila; Avraham, Roy; Weiss, Shay; Paran, Nir; Israely, Tomer

doi:10.3390/v14020189

Cited by 26 publications

(20 citation statements)

References 57 publications

(65 reference statements)

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“…Moreover, inhibition of TLR3 leads to decreased production of inflammatory cytokines and IFNs in SARS-CoV-2–infected Calu-3/MRC-5 multicellular spheroids [ 26 ]. Similarly, administration of poly I:C improves survival in K18-hACE2 transgenic mice during SARS-CoV-2 infection by reducing viral load and inflammation in the lungs and brains [ 27 ]. These findings suggest there may be a protective effect of TLR3 signaling during COVID-19.…”

Section: Innate Immune Sensing and Signaling In Response To Sars-cov-2mentioning

confidence: 99%

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Karki

Kanneganti

2022

J Transl Med

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The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated innate immune responses can induce aberrant inflammation that is detrimental to the host. Therefore, careful innate immune regulation is critical during infections. The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in global morbidity and mortality as well as socio-economic stresses. Innate immune sensing of SARS-CoV-2 by multiple host cell pattern recognition receptors leads to the production of various pro-inflammatory cytokines and the induction of inflammatory cell death. These processes can contribute to cytokine storm, tissue damage, and acute respiratory distress syndrome. Here, we discuss the sensing of SARS-CoV-2 to induce innate immune activation and the contribution of this innate immune signaling in the development and severity of COVID-19. In addition, we provide a conceptual framework for innate immunity driving cytokine storm and organ damage in patients with severe COVID-19. A better understanding of the molecular mechanisms regulated by innate immunity is needed for the development of targeted modalities that can improve patient outcomes by mitigating severe disease.

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Section: Innate Immune Sensing and Signaling In Response To Sars-cov-2mentioning

confidence: 99%

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Karki

Kanneganti

2022

J Transl Med

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“…The TLR3/MDA5 synthetic agonist Poly (I: C) was shown to be effective against lethal doses of SARS-CoV-2 in K18-HACE2 transgenic mice. Early Poly (I: C) treatment accompanied by reduced viral load, prevention of cytokine storms in lung and brain cells, and increased macrophage and NK cell levels which resulted in an 83% survival rate in mice with long-term immunization ( Tamir et al, 2022 ). Therefore, initiating lung innate immunity with Poly (I: C) or similar methods can provide effective and safe protection against SARS-CoV-2 infection.…”

Section: Tlrs Sensing Of Sars-cov-2mentioning

confidence: 99%

Toll-like receptor (TLRs) agonists and antagonists for COVID-19 treatments

Liu

Yang

et al. 2022

Front. Pharmacol.

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Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) rapidly infects humans and animals which make coronavirus disease 2019 (COVID-19) a grievous epidemic worldwide which broke out in 2020. According to data analysis of the other coronavirus family, for instance severe acute respiratory syndrome SARS coronavirus (SARS-CoV), can provide experience for the mutation of SARS-CoV-2 and the prevention and treatment of COVID-19. Toll-like receptors (TLRs) as a pattern recognition receptor (PRRs), have an indispensable function in identifying the invader even activate the innate immune system. It is possible for organism to activate different TLR pathways which leads to secretion of proinflammatory cytokines such as Interleukin 1 (IL-1), Interleukin 6 (IL-6), Tumor necrosis factor α (TNFα) and type Ⅰ interferon. As a component of non-specific immunity, TLRs pathway may participate in the SARS-CoV-2 pathogenic processes, due to previous works have proved that TLRs are involved in the invasion and infection of SARS-CoV and MERS to varying degrees. Different TLR, such as TLR2, TLR4, TLR7, TLR8 and TLR9 probably have a double-sided in COVID-19 infection. Therefore, it is of great significance for a correctly acknowledging how TLR take part in the SARS-CoV-2 pathogenic processes, which will be the development of treatment and prevention strategies.

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“…In contrast, the TLR3 agonist Poly(I:C) induced protective inflammatory cytokine expression, including IL-10 and TNF-α 56,58 , and reduced the inflammatory score and mRNA expression of SARS-CoV-2 proteins. These results support a protective, anti-viral effect in addition to increased microvascular density and reduced pulmonary artery MWT and EC apoptosis.…”

Section: Discussionmentioning

confidence: 89%

A role for Toll-like receptor 3 in lung vascular remodeling associated with SARS-CoV-2 infection

Farkas

Bogamuwa

Piper

et al. 2023

Preprint

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Cardiovascular sequelae of severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) disease 2019 (COVID-19) contribute to the complications of the disease. One potential complication is lung vascular remodeling, but the exact cause is still unknown. We hypothesized that endothelial TLR3 insufficiency contributes to lung vascular remodeling induced by SARS-CoV-2. In the lungs of COVID-19 patients and SARS-CoV-2 infected Syrian hamsters, we discovered thickening of the pulmonary artery media and microvascular rarefaction, which were associated with decreased TLR3 expression in lung tissue and pulmonary artery endothelial cells (ECs). In vitro, SARS-CoV-2 infection reduced endothelial TLR3 expression. Following infection with mouse-adapted (MA) SARS-CoV-2, TLR3 knockout mice displayed heightened pulmonary artery remodeling and endothelial apoptosis. Treatment with the TLR3 agonist polyinosinic:polycytidylic acid reduced lung tissue damage, lung vascular remodeling, and endothelial apoptosis associated with MA SARS-CoV-2 infection. In conclusion, repression of endothelial TLR3 is a potential mechanism of SARS-CoV-2 infection associated lung vascular remodeling and enhancing TLR3 signaling is a potential strategy for treatment.

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Induction of Innate Immune Response by TLR3 Agonist Protects Mice against SARS-CoV-2 Infection

Cited by 26 publications

References 57 publications

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Toll-like receptor (TLRs) agonists and antagonists for COVID-19 treatments

A role for Toll-like receptor 3 in lung vascular remodeling associated with SARS-CoV-2 infection

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