COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis

Sohn, Kyung Mok; Lee, Sung-Gwon; Kim, Hyeon Ji; Cheon, Shinhye; Jeong, Hyeongseok; Lee, Joo-Yeon; Kim, In Soo; Silwal, Prashanta; Kim, Young Jae; Paik, Seungwha; Chung, Chaeuk; Park, Chungoo; Kim, So Hyun; Jo, Eun-Kyeong

doi:10.3346/jkms.2020.35.e343

Cited by 175 publications

(186 citation statements)

References 50 publications

(66 reference statements)

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“…(43). Furthermore, also the activation of TLR4 (at the outer membrane) by SARS-CoV-2 has been indicated by a recent study (38). TLR4 also can be activated by LPD derived from bacterial co-infection or secondary bacterial infections, which have been found in up to 14% of SARS-CoV-2 infected patients (45).…”

Section: Inhibition Of Nf-kb Can Inhibit Both Virus-induced and Lps-imentioning

confidence: 89%

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

Kircheis¹,

et al. 2020

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Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

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Section: Inhibition Of Nf-kb Can Inhibit Both Virus-induced and Lps-imentioning

confidence: 89%

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

Kircheis¹,

et al. 2020

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“…In COVID-19 patients, Sohn et al recently reported that the expression of TLR4 itself and its downstream signalling mediators were significantly upregulated in peripheral blood mononuclear cells, compared to those in healthy controls [ 122 ]. The inflammatory molecules found to be upregulated include CD14, MyD88, Mal (also known as TIRAP), TRAF6, IRAK1, and TICAM (also known as TRIF).…”

Section: Evidence For Sars-cov-1 and Sars-cov-2 Proteins Binding Tmentioning

confidence: 99%

“…This shows the importance of the HMGB1/RAGE/TLR4 axis in mediating inflammation [ 126 ]. Interestingly, it has also been recently shown that the alarmin S100A9, a DAMP and TLR4 ligand, is a reliable biomarker in severe/critically ill COVID-19 patients [ 122 ].…”

Section: Evidence For Sars-cov-1 and Sars-cov-2 Proteins Binding Tmentioning

confidence: 99%

COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation

Aboudounya

Heads

2021

Mediators of Inflammation

267

271

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Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and triggers the production of type I interferons and proinflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently, the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. 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. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.

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“…TLR4 has been identified as a potential receptor for the outer protein spike of SARS-CoV-2 [ 159 ]. It has been reported that COVID-19 patients upregulate TLR4-mediated signaling, which exacerbates SARS [ 160 ]. The more critically ill patients present highly increased S100 calcium-binding protein A9 (S100A9) blood levels, a TLR4-recognized DAMP.…”

Section: Coronavirus Disease-2019 (Covid-19)mentioning

confidence: 99%

Phosphatases in toll-like receptors signaling: the unfairly-forgotten

et al. 2021

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Over the past 2 decades, pattern recognition receptors (PRRs) have been shown to be on the front line of many illnesses such as autoimmune, inflammatory, and neurodegenerative diseases as well as allergies and cancer. Among PRRs, toll-like receptors (TLRs) are the most studied family. Dissecting TLRs signaling turned out to be advantageous to elaborate efficient treatments to cure autoimmune and chronic inflammatory disorders. However, a broad understanding of TLR effectors is required to propose a better range of cures. In addition to kinases and E3 ubiquitin ligases, phosphatases emerge as important regulators of TLRs signaling mediated by NF-κB, type I interferons (IFN I) and Mitogen-Activated Protein Kinases signaling pathways. Here, we review recent knowledge on TLRs signaling modulation by different classes and subclasses of phosphatases. Thus, it becomes more and more evident that phosphatases could represent novel therapeutic targets to control pathogenic TLRs signaling. Graphic abstract

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COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis

Cited by 175 publications

References 50 publications

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation

Phosphatases in toll-like receptors signaling: the unfairly-forgotten

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