Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

Brandão, Simone Cristina Soares; Ramos, Júlia de Oliveira Xavier; Dompieri, Luca Terracini; Godoi, Emmanuelle Tenório Albuquerque Madruga; Figueiredo, José Luiz; Sarinho, Emanuel Sávio Cavalcanti; Chelvanambi, Sarvesh; Aikawa, Masamichi

doi:10.1016/j.cytogfr.2020.09.002

Cited by 81 publications

(83 citation statements)

References 149 publications

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“…However, they do mention that some TLR4 antagonists including Eritoran and TAK242 (both proposed here) were used successfully in the treatment of inflammation associated with cancer, rheumatoid arthritis, and other inflammatory diseases ([ 151 ] and references therein). Based on our proposal (see Disclosure: DOI) and Choudhury and Mukherjee [ 30 ], another recent report speculates on the hypothesis that the TLR4 signalling pathway provides opportunities for the targeting of TLR4 by antagonists in severe COVID-19 patients with cardiometabolic complications provided that the involvement of TLR4 is proven [ 152 ]. Based on the comprehensive and detailed evidence reviewed here, we support in principle the trial of TLR4 antagonists in the treatment of severe COVID-19 infections to (1) reduce the severe inflammation, particularly in the lungs and heart, but also systemically (2) block the entry mechanism involving ACE2 upregulation that we have proposed.…”

Section: Possible Therapeutic Options For Treating Covid-19 Whichmentioning

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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Section: Possible Therapeutic Options For Treating Covid-19 Whichmentioning

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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“…SARS-CoV-2 mediated myocardial apoptosis, cardiogenic shock, myocardial ischemia and inflammatory injury were related to the down-regulation of ACE2 in the myocardium [ [51] , [52] ]. The spike protein of SARS-CoV-2 might bind to TLR4 to trigger transmembrane stimulation [ [53] , [54] ]. Then, TLR4 activated interferon (IFN)-regulatory factors (IRF3 and IRF7), leading to increased expression of one of the hub genes IFNB1 and further enhancive the secretion of IFN-β [ [55] , [56] ].…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and RNA-sequencing reveal the molecular mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction

Zhang

Zhu

et al. 2021

Computers in Biology and Medicine

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Background Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20%–30% of patients hospitalized with COVID-19 have evidence of cardiac dysfunction. Xuebijing injection is a compound injection containing five traditional Chinese medicine ingredients, which can protect cells from SARS-CoV-2-induced cell death and improve cardiac function. However, the specific protective mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction remains unclear. Methods The therapeutic effect of Xuebijing injection on COVID-19 was validated by the TCM Anti COVID-19 (TCMATCOV) platform. RNA-sequencing (RNA-seq) data from GSE150392 was used to find differentially expressed genes (DEGs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. Data from GSE151879 was used to verify the expression of Angiotensin I Converting Enzyme 2 (ACE2) and central hub genes in both human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) and adult human CMs with SARS-CoV-2 infection. Results A total of 97 proteins were identified as the therapeutic targets of Xuebijing injection for COVID-19. There were 22 DEGs in SARS-CoV-2 infected hiPSC-CMs overlapped with the 97 therapeutic targets, which might be the therapeutic targets of Xuebijing injection on COVID-19-induced cardiac dysfunction. Based on the bioinformatics analysis, 7 genes (CCL2, CXCL8, FOS, IFNB1, IL-1A, IL-1B, SERPINE1) were identified as central hub genes and enriched in pathways including cytokines, inflammation, cell senescence and oxidative stress. ACE2, the receptor of SARS-CoV-2, and the 7 central hub genes were differentially expressed in at least two kinds of SARS-CoV-2 infected CMs. Besides, FOS and quercetin exhibited the tightest binding by molecular docking analysis. Conclusion Our study indicated the underlying protective effect of Xuebijing injection on COVID-19, especially on COVID19-induced cardiac dysfunction, which provided the theoretical basis for exploring the potential protective mechanism of Xuebijing injection on COVID19-induced cardiac dysfunction.

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“…Similarly, there have been studies claiming an important role of TLR4 in SARS-CoV-2, as in silico studies identified TLR4 as very likely to respond to spike proteins of SARS-CoV-2 [ 49 ]. Interestingly, TLR4 is also associated with cardiometabolic comorbidities such as obesity and hypertension, which are known risk factors for severe COVID with hyperinflammation [ 50 ]. Furthermore, TLR4-deficient mice were less susceptible to acute respiratory distress syndrome (ARDS) upon inhalation trauma [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

Thada

Horváth

et al. 2021

IJMS

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The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB.

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Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

Cited by 81 publications

References 149 publications

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

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

Network pharmacology and RNA-sequencing reveal the molecular mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction

Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

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