Dual Targeting of Toll-Like Receptor 4 and Angiotensin-Converting Enzyme 2: A proposed Approach to SARS-CoV-2 Treatment

Gadanec, Laura Kate; Qaradakhi, Tawar; McSweeney, Kristen Renee; Ali, Benazir Ashiana; Zulli, Anthony; Apostolopoulos, Vasso

doi:10.2217/fmb-2021-0018

Cited by 26 publications

(24 citation statements)

References 49 publications

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“…The excessive in ammatory response during COVID-19 infection that is the major cause of death in these patients is closely related to the Toll-Like Receptor-binding e cacy of SARS-CoV-2, which causes the release of pro-IL-1β and in ammasome activation, followed by the production of active IL-1β as a main mediator of fever and lung in ammation [29]. Uncontrolled activation of TLR4 in ammatory signals has been reported to involve in immunopathological features of COVID-19 infection [30]. TLRs-mediated signaling in humans triggers markedly extensive cytokine and chemokine release [31], which is a characteristic of COVID-19 disease.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Impact on COVID-19 Patients Immune System, an Ex Vivo Study

Saraei

Malekpour

Hazrati

et al. 2021

Preprint

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Current clinical management approaches for COVID-19 patients are generally based on supportive treatment, which mainly includes respiratory support and restricted fluid input, which is currently a subject of much debate. Systemic Inflammation caused by SARS-CoV-2 may be related to various extrapulmonary comorbidities such as cytokine-mediated neuroinflammation leading to both non-neuronal and neurological consequences in COVID-19. Mesenchymal stem cells (MSCs) are adult stem cells with multipotent properties suitable for medical applications that have been reported as potential therapies in the setting of lung diseases. The immunosuppressive properties of MSCs provide a strong rationale to explore their potential beneficial effects on immune events in COVID-19. Multiple in vivo studies have demonstrated the capability of MSCs to prevent inflammatory responses and reduce lung damage. Recently, the use of MSCs in treating COVID-19 disease has improved long-term pulmonary function, but the specific mechanisms by which MSCs inhibit the severe inflammatory response induced by SARS-CoV-2 have not been elucidated. To the best of our knowledge, this is the first work describing the regulatory effects of MSCs on peripheral blood mononuclear cells (PBMCs) derived from patients with COVID-19 by measuring the pro-inflammatory and anti-inflammatory cytokines expression and secretion. We also examined the effects on the methylation of genes normally suppressed by DNA methylation in PBMCs. Our result showed that MSCs exerted an immune regulatory function on PBMCs in culture, skewing toward a type-2 response. This occurs by a mechanism consistent with a reduction in inflammatory factors (TNF-α, IL-1β, IL-6, IL-18, and IFNγ) protein and mRNA expression levels. In contrast, the anti-inflammatory cytokines (IL-4 and IL-10) increased following co-culture with MSCs. Consistent with these findings, the DNA methylation status of these immune genes seemed relevant to their expression pattern, except for GATA3, IL-1β, and IFNγ genes which showed no significant differences in methylation level between PBMCs with and without MSC exposure. Moreover, in co-culture interaction, MSCs modulated the Th1/Th2 cells in PBMCs compared to unstimulated PBMCs. These data demonstrate that MSCs can exert important immunomodulatory functions that affect virus-associated cytokine storms in pulmonary tissue during the severe respiratory stage.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Impact on COVID-19 Patients Immune System, an Ex Vivo Study

Saraei

Malekpour

Hazrati

et al. 2021

Preprint

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“… 23 A link between TLR4 signalling in host cells and SARS-CoV-2-mediated inflammation has been observed via viral spike protein binding to host TLR4, and a therapeutic strategy targeting TLR4 inhibition and ACE-2 activation has been suggested. 18 , 19 , 24 Our suggestion is that there is interplay between opioids, ACE-2, TLR4 and SARS-CoV-2. A TLR4–opioid ligand interferes with SARS-CoV-2-TLR4-ACE-2 signalling ( Table 1 ).…”

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confidence: 80%

“…25 9. A strategy of selective targeting of TLR4-SARS-CoV-2 spike protein interaction using competitive TLR4 antagonists as a way of treating COVID-19 has been proposed 23 , 24 10. A combination therapy of diminazene aceturate (an ACE-2 activator) and novel antagonist resatorvid (a TLR4 inhibitor) has been proposed as a promising therapy for effective treatment of COVID-19 24 11.…”

mentioning

confidence: 99%

“… A strategy of selective targeting of TLR4-SARS-CoV-2 spike protein interaction using competitive TLR4 antagonists as a way of treating COVID-19 has been proposed 23 , 24 10. A combination therapy of diminazene aceturate (an ACE-2 activator) and novel antagonist resatorvid (a TLR4 inhibitor) has been proposed as a promising therapy for effective treatment of COVID-19 24 11. While it is recommended that untreated opioid-dependent individuals should be promptly entered into opioid substitution treatment 26 , related drugs that do not activate opioid receptors such as opioid antagonists (e.g.…”

mentioning

confidence: 99%

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Therapeutic potential of long-acting opioids and opioid antagonists for SARS-CoV-2 infection

Eagleton¹,

Stokes²,

Fenton³

et al. 2021

British Journal of Anaesthesia

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“…SARS-CoV-2 typically enters the body through the nose and throat. It then binds to and invades the cells of the upper respiratory tract which are rich in angiotensin-converting enzyme 2 (ACE2) receptor [6]; although recently it has been shown that SARS-CoV-2 can also enter host cells via several different receptors [7][8][9]. If the individual's immune system is able to repel the virus during this initial phase (via the generation of neutralization antibodies), it is able to move down to infect the lung parenchyma, where it becomes significantly more dangerous.…”

mentioning

confidence: 99%

COVID-19 Vaccines in the Pipeline, Are Antibodies Adequate?

Hossain

Hassanzadeganroudsari

Feehan

et al. 2021

Vaccines

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Dual Targeting of Toll-Like Receptor 4 and Angiotensin-Converting Enzyme 2: A proposed Approach to SARS-CoV-2 Treatment

Cited by 26 publications

References 49 publications

Mesenchymal Stem Cells Impact on COVID-19 Patients Immune System, an Ex Vivo Study

Mesenchymal Stem Cells Impact on COVID-19 Patients Immune System, an Ex Vivo Study

Therapeutic potential of long-acting opioids and opioid antagonists for SARS-CoV-2 infection

COVID-19 Vaccines in the Pipeline, Are Antibodies Adequate?

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