Role of toll-like receptor 7/8 pathways in regulation of interferon response and inflammatory mediators during SARS-CoV2 infection and potential therapeutic options

Dyavar, Shetty Ravi; Singh, R. D.; Emani, Rohini; Pawar, Ganesh P.; Chaudhari, Vinod D.; Podany, Anthony T.; Avedissian, Sean N.; Fletcher, Courtney V.; Salunke, Deepak B.

doi:10.1016/j.biopha.2021.111794

Cited by 32 publications

(33 citation statements)

References 104 publications

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“…Further studies are needed to clarify the involvement of TLR4 as a co-or receptor for SARS-CoV-2. Moreover, TLRs are involved in the activation of the immune response causing a cytokine storm in COVID-19 patients, where TLR-3, -7, -8 through viral RNA recognition triggers the activation of JAK/ STAT, NF-kB, AP-1 signaling pathways resulting in the amplification of pro-inflammatory cytokines (152,153). Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153).…”

Section: Human Toll-like Receptors (Tlrs)mentioning

confidence: 99%

“…Moreover, TLRs are involved in the activation of the immune response causing a cytokine storm in COVID-19 patients, where TLR-3, -7, -8 through viral RNA recognition triggers the activation of JAK/ STAT, NF-kB, AP-1 signaling pathways resulting in the amplification of pro-inflammatory cytokines (152,153). Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153). In this sense, HCQ can inhibit endosomal TLR3, -7, -8, and -9 signaling, controlling inflammation in COVID-19 patients and mitigating the detrimental effects of viral infection (152,153).…”

Section: Human Toll-like Receptors (Tlrs)mentioning

confidence: 99%

“…Thus, TLR7/8 antagonist drugs (Hydroxychloroquine, HCQ; a TLR blocker) could limit SARS-CoV-2 infection (152,153). In this sense, HCQ can inhibit endosomal TLR3, -7, -8, and -9 signaling, controlling inflammation in COVID-19 patients and mitigating the detrimental effects of viral infection (152,153).…”

Section: Human Toll-like Receptors (Tlrs)mentioning

confidence: 99%

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Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

et al. 2021

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Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.

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Section: Human Toll-like Receptors (Tlrs)mentioning

confidence: 99%

Section: Human Toll-like Receptors (Tlrs)mentioning

confidence: 99%

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Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

et al. 2021

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“…The host response and cytokine profile in COVID-19 is distinct from that of other b-coronaviruses and influenza A viruses (10). In particular, reduced type I interferon levels are associated with severe COVID-19, suggesting disease severity may be due to impaired viral clearance and uncontrolled viral replication (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Cytokine Profile in Patients With Mild to Critical COVID-19

et al. 2021

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The cytokine release syndrome has been proposed as the driver of inflammation in coronavirus disease 2019 (COVID-19). However, studies on longitudinal cytokine profiles in patients across the whole severity spectrum of COVID-19 are lacking. In this prospective observational study on adult COVID-19 patients admitted to two Hong Kong public hospitals, cytokine profiling was performed on blood samples taken during early phase (within 7 days of symptom onset) and late phase (8 to 12 days of symptom onset). The primary objective was to evaluate the difference in early and late cytokine profiles among patient groups with different disease severity. The secondary objective was to assess the associations between cytokines and clinical endpoints in critically ill patients. A total of 40 adult patients (mild = 8, moderate = 15, severe/critical = 17) hospitalized with COVID-19 were included in this study. We found 22 cytokines which were correlated with disease severity, as proinflammatory Th1-related cytokines (interleukin (IL)-18, interferon-induced protein-10 (IP-10), monokine-induced by gamma interferon (MIG), and IL-10) and ARDS-associated cytokines (IL-6, monocyte chemoattractant protein-1 (MCP-1), interleukin-1 receptor antagonist (IL-1RA), and IL-8) were progressively elevated with increasing disease severity. Furthermore, 11 cytokines were consistently different in both early and late phases, including seven (growth-regulated oncogene-alpha (GRO-α), IL-1RA, IL-6, IL-8, IL-10, IP-10, and MIG) that increased and four (FGF-2, IL-5, macrophage-derived chemokine (MDC), and MIP-1α) that decreased from mild to severe/critical patients. IL-8, followed by IP-10 and MDC were the best performing early biomarkers to predict disease severity. Among critically ill patients, MCP-1 predicted the duration of mechanical ventilation, highest norepinephrine dose administered, and length of intensive care stay.

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“…Application of adjuvant with RBD-NP can enhance neutralizing antibody production and CD4 T cell responses through TLRs. It is understood that optimal IFN production and controlled inflammation are necessary for reducing COVID-19 pathogenesis caused by excessive cytokine production, which could be achieved through the regulation of the TLR-mediated response [114,115]. Therefore, it is critical to obtain a clear understanding of TLR interactions in SARS-CoV-2 infection, which may provide a new basis for the development of therapeutic and preventive approaches to fight the disease, including a TLR agonist-adjuvanted SARS-CoV-2 vaccine.…”

Section: Discussionmentioning

confidence: 99%

An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

Kayesh

Kohara

Tsukiyama-Kohara

2021

Viruses

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to coronavirus disease (COVID-19), a global health pandemic causing millions of deaths worldwide. However, the immunopathogenesis of COVID-19, particularly the interaction between SARS-CoV-2 and host innate immunity, remains unclear. The innate immune system acts as the first line of host defense, which is critical for the initial detection of invading pathogens and the activation and shaping of adaptive immunity. Toll-like receptors (TLRs) are key sensors of innate immunity that recognize pathogen-associated molecular patterns and activate downstream signaling for pro-inflammatory cytokine and chemokine production. However, TLRs may also act as a double-edged sword, and dysregulated TLR responses may enhance immune-mediated pathology, instead of providing protection. Therefore, a proper understanding of the interaction between TLRs and SARS-CoV-2 is of great importance for devising therapeutic and preventive strategies. The use of TLR agonists as vaccine adjuvants for human disease is a promising approach that could be applied in the investigation of COVID-19 vaccines. In this review, we discuss the recent progress in our understanding of host innate immune responses in SARS-CoV-2 infection, with particular focus on TLR response. In addition, we discuss the use of TLR agonists as vaccine adjuvants in enhancing the efficacy of COVID-19 vaccine.

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Role of toll-like receptor 7/8 pathways in regulation of interferon response and inflammatory mediators during SARS-CoV2 infection and potential therapeutic options

Cited by 32 publications

References 104 publications

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Longitudinal Cytokine Profile in Patients With Mild to Critical COVID-19

An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

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